ORIGINAL ARTICLE 
Annals of Nuclear Medicine Vol. 12, No. 5, 287-292. 1998 
Reverse redistribution of Tc-99m-tetrofosmin in exercise myocardial SPECT in patients with hypertrophic cardiomyopathy 
Hiroki SuGIHARA,* Yoko TANIGUCHI,** Noriyuki KlNOSHITA,** Tomoki NAKAMURA,** Satoshi HIRASAKI,** Akihiro AzUMA,** Yo UsHUIMA,* Chio OKUYAMA,* Masao NAKAGAWA** and Tomoho MAEDA* 
*Department of Radiology and **Second Department of Medicine. Kyoto Prefectural University of Medicine 
We examined the usefulness of Tc-99m-tetrofosmin in detecting exercise induced perfusion abnormalities in patients with hypertrophic cardiomyopathy (HCM) and to clarify time-related changes in myocardial distribution of Tc-99m-tetrofosmin after a single injection. We studied 44 consecutive patients with HCM by means of exercise/rest Tc-99m-tetrofosmin single photon emission computed tomography (SPECT). After injecting 370 MBq of Tc-99m-tetrofosmin at the peak exercise, the early SPECT imaging was performed at 30 min (EX-30) and the delayed imaging at 180 min (EX-180). Immediately after the delayed imaging, 740 MBq of Tc-99m-tetrofosmin was injected in the resting state, and the rest SPECT imaging was performed 30 min later. Exercise-induced regional perfusion defects and/or apparent reversible left ventricular cavity dilation were identified in 26 (68.2%) of the 44 patients. When EX-30 images and EX-180 images were compared, reverse redistribution was confirmed in 36 patients (81.8%). Reverse redistribution was detected most frequently in the septal portion of the anterior wall, followed by the septal portion of the posterior wall and the septum. Exercise/rest Tc-99m-tetrofosmin myocardial imaging was a useful method for assessing myocardial perfusion abnormalities in patients with HCM. Reverse redistribution was detected very frequently on early and delayed images of exercise. We assumed that reverse redistribution may reflect a retention disorder of Tc-99m-tetrofosmin caused by some metabolic dysfunction of myocytes. 
Key words: Tc-99m-tetrofosmin, hypertrophic cardiomyopathy, myocardial ischemia, reverse redistribution
INTRODUCTION 
Tc-99m-TETRoFosMlN is a myocardial perfusion agent with favorable imaging characteristics.1 Many studies have reported on the clinical usefulness of stress Tc-99m-tetrofosmin myocardial scintigraphy to detect coronary artery disease.1-5 This tracer was reported to be rapidly cleared from the blood after intravenous administration and taken up by the myocardium and other tissues. Once Tc-99m-tetrofosmin is taken up by the myocardium, it is considered that its clearance is relatively slow, and that redistribution does not occur for several hours 6 Although myocardial images with Tc-99m-tetrofosmin are believed to be uninfluenced by the starting time of acquisition after injection, we noted that myocardial images with this tracer often showed more reduced tracer uptake on delayed images than on early images in patients with hyper-trophic cardiomyopathy, acute myocardial infarction or complete left bundle branch block.7 On the other hand, myocardial ischemia may play an important role in the pathophysiology and the natural history of hypertrophic cardiomyopathy, and exercise Tl-201 myocardial single photon emission computed tomography (SPECT) has provided a noninvasive means of identifying myocardial perfusion abnormalities.8-12 A few studies have reported the assessment of myocardial perfusion abnormalities in patients with hypertrophic cardiomyopathy with exercise/rest Tc-99m-tetrofosmin SPECT.12 The present study was performed to determine the usefulness of Tc-99m-tetrofosmin in detecting exercise-induced perfusion abnormalities in patients with hypertrophic cardiomyopathy and to clarify time-related changes in myocardial distribution of Tc-99m-tetrofosmin after a single injection. 
METHODS 
Patient population The subjects were 44 patients with hypertrophic cardiomyopathy (average age: 55+-10 years, 32 males and 12 females). The diagnosis of hypertrophic cardiomyopathy was based on clinical findings and the echocardiographic 
demonstration of unexplained left ventricular hypertro-phy. Of the 44 patients, 25 were asymptomatic, 17 had mild symptoms (New York Heart Association functional class II), and 2 had moderate symptoms (class III). There were 36 non-obstructive cases and 8 obstructive cases, and the maximum wall thickness and left ventricular % shortening fraction measured by 2 dimensional echocardiography was 23+-7 mm and 49+-6%, respectively. All patients had normal coronary angiographic findings. Twenty-three patients received either a Ca channel blocker or a b-blocker and 21 patients did not take medication. Drug administration was suspended for 48 hours before myocardial scintigraphy . 
Exercise/rest Tc-99m-tetrofosmin SPECT 
All patients underwent bicycle exercise according to a standard multistage exercise protocol with continuous monitoring of heart rate, blood pressure, ECG and symptoms. At peak exercise, 370 MBq of Tc-99m-tetrofosmin was intravenously injected and the patient continued to exercise for an additional 1 minute and 30 seconds. Immediately after the injection, each patient drank a glass of milk to accelerate the hepatobiliary clearance of the tracer. SPECT data acquisition was performed twice; early and delayed imaging started 30 and 180 minutes post injection, respectively (EX-30 and EX- 180). After EX-180 imaging, 740 MBq of Tc-99m-tetrofosmin was injected intravenously at rest, and each patient drank another glass of milk. SPECT imaging (Rest) was per-formed 30 minutes later13 (Fig. 2). A digital gamma camera (Prism 2000XP; Picker International Inc., Ohio or GCA 901A; Toshiba Co. Ltd., Tokyo) equipped with a low energy, high resolution, parallel-hole collimator was used for SPECT imaging. Projection images was taken for 30-sec 6 deg. increments over 1 80 deg. circular orbits beginning at 45 deg. left posterior oblique projection and ending at 45 deg. right anterior oblique projection. After a preprocedure with a Butterworth filter, transverse axial tomograms of 5.3 mm thickness per slice were reconstructed with a Shepp-Logan filter without correction for attenuation or scatter. The left ventricle was divided into 17 segments as follows: the basal and middle regions of the short axis were divided into 8 segments, and the apical region of the vertical long axis made up the 17th segment. A 4-point scoring system was used to evaluate the regional myocar-dial uptake of the tracer: defect = 3, moderately decreased = 2, mildly decreased = 1 , and normal = 0 (Fig. 1). A score of 2 or 3 was considered to represent a defect. To compare EX-30 and EX-180 images, redistribution was defined as a segment showing an improved score on the EX-180 images, and reverse redistribution was defined as a segment showing a worsened score. The images were analyzed by 2 experienced observers in a blind manner. 
RESULTS 
(1) Regional perfusion defects were identified in 30 (68.2%) of the 44 study patients on the EX-30 images. Fifteen of the 30 patients had perfusion abnormalities on the EX-30 images that completely normalized on the Rest images. Partially reversible defects were observed in 8, and fixed defects were observed in 7 of the 30 patients (Figs. 2 and 3). 
(2) Regarding EX-30 and Rest images, apparent reversible left ventricular cavity dilation was observed on the short axial images of 9 of the 44 patients (20.5%) (Fig. 4). Completely or partially reversible defects were absent in 3 of the 9 patients. Exercise-induced regional perfusion defects and/or apparent reversible left ventricular cavity dilation was detected in 26 of the 44 patients (59.1 %). 
(3) When the EX-30 and EX-180 of each patient were compared, no changes were detected in 5 patients (11.4%), redistribution was confirmed in 3 patients (6.8%) and reverse redistribution was confirmed in 36 patients (81.8%) (Figs. 3 and 5). 
(4) When the EX-30 and EX-180 were compared in all 748 segments, no changes were detected in 511 segments (68.3%), redistribution was confirmed in 17 segments (2.3%) and reverse redistribution was confirmed in 220 segments (29.4%) (Fig. 6). 
(5) Reverse redistribution was detected most frequently in the septal portion of the anterior wall, followed by the septal portion of the posterior wall, and the septum (Fig. 7). 
DISCUSSION 
Our study indicated that exercise/rest Tc-99m-tetro-fosmin images often showed reversible defects in patients with hypertrophic cardiomyopathy, as well as exercise Tl-201 images,13 Furthermore, we demonstrated that the time-related changes in myocardial distribution of Tc-99m-tetrofosmin after a single injection was evident in patients with hypertrophic cardiomyopathy. This re-verse redistribution was frequently observed in the septal portion of the anterior and posterior walls and septal wall, where myocardial architectural abnormalities may be most severe in patients with hypertrophic cardiomyopathy.14 Many studies have reported that myocardial ischemia plays an important role in the natural history of hyper-trophic cardiomyopathy.15-17 Exercise Tl-201 myocar-dial scintigraphy has provided a noninvasive means of identifying myocardial perfusion abnormalities in pa-tients with hypertrophic cardiomyopathy.7,8,9,17 Tc-99m-tetrofosmin has now been introduced into clinical routine. The present study was performed to determine the useful-ness of Tc-99m-tetrofosmin in detecting exercise-induced perfusion abnormalities in patients with hypertrophic cardiomyopathy. Once Tc-99m-tetrofosmin is taken up by the myocardium, it is retained for a relatively long 
time. It has been thought that the time-related changes in myocardial distribution of the tracer do not occur for several hours.3,5 Although the myocardial distribution of Tc-99m-tetrofosmin is believed to be uninfluenced by the starting time of acquisition after injection, serial changes in its distribution after a single injection were also ana-lyzed. 
(1) Detection ofmyocardialperfusion abnormalities by exercise/rest Tc-99m-tetrofosmin myocardial SPECT Previous studies demonstrated that Tc-99m-tetrofosmin is rapidly cleared from the blood and accumulates in the myocardium in proportion to regional myocardial perfu-sion after intravenous administration. In the present study, since EX-30 and Rest images represented myocardial perfusion during exercise and at rest, respectively, exer-cise-induced regional myocardial perfusion abnormali-ties were detected even in the absence of coronary steno-sis in 56.7% of the patients. Apparent left ventricular cavity dilation during exercise was observed in 31.8% of patients. O'Gara et al. suggested that apparent cavity dilation in a Tl-201 study after exercise was caused by subendocardial hypoperfusion 7 Cannon et al. reported that apparent cavity dilation during exercise Tl-201 scintigraphy indicates ischemiarelated changes in left ven-tricular filling, with elevation in diastolic pressures and endocardial compression 18 If exercise-induced regional defects and/or apparent cavity dilation during exercise were to be myocardial perfusion abnormalities, then exercise-induced myocardial perfusion abnormalities were confirmed in 59.1% of the patients. The frequency of HCM showing exercise-induced myocardial perfusion abnormalities with Tc-99m-tetrofosmin was similar to that with Tl-201.7 As myocardial perfusion abnormalities commonly occur in patients with hypertrophic cardiomy-opathy even in the absence of angiographical coronary stenosis, whether Tl-201 or Tc-99m-tetrofosmin is supe-rior in detecting myocardial perfusion abnormalities in patients with hypertrophic cardiomyopathy is difficult to determine. Nonetheless, Tc-99m-tetrofosmin may be con-sidered to be excellent because myocardial images with Tl-201 often show decreased uptake in the inferior wall by attenuation due to its low-energy photons, and because the image quality of Tc-99m-tetrofosmin SPECT is superior to that of Tl-201 SPECT. Further studies are nece-sary to investigate whether or not differences in the myocardial images of patients with hypertrophic cardi-omyopathy are caused by the differences in the mecha-nism of uptake into myocytes and the physical properties of the 2 tracers. 
(2) Early and delayed exercise Tc-99m-tetrofosmin SPECT Although the myocardial uptake of Tc-99m-tetrofosmin is mainly dependent on the blood flow, the precise mecha-nism of uptake of this tracer into myocytes has not been elucidated. The results of a recent study on isolated rat heart suggested that the uptake by myocytes is not achieved by cation channel transport, as it is for TI-201 , but rather is achieved by a metabolism-dependent process. The most likely uptake mechanism is thought to be potential driven diffusion on the lipophilic cations across the sar-colemmal and mitochondrial membranes.19,20 Once Tc-99m-tetrofosmin is taken up by the myocardium, it is retained for a relatively long time. It has been thought that the time-related changes in myocardial distribution of the tracer do not occur for 3 to 4 hours.3,5 Since the biokinetics of Tc-99m-tetrofosmin have not been fully clarified, in our facilities all SPECT data of Tc-99m-tetrofosmin were obtained twice; an early image 30 min and a delayed image 180 min after administration of this tracer. We noted cases showing a significant difference between early and delayed images, including those with acute myocardial infarction and complete left bundle branch block.7 Hypertrophic cardiomyopathy is one of the dis-eases with this unusual finding. Reverse redistribution of Tc-99m-tetrofosmin was con-firmed in 81.8% of patients with hypertrophic cardiomyopathy. Reverse redistribution was frequently observed in the septal portion of the anterior and posterior walls and the septum. The mechanism of reverse redistribution of Tc-99m-tetrofosmin that occurred in patients with hyper-trophic cardiomyopathy is not known. Kuribayashi et al. reported that in patients with hypertrophic cardiomyopathy, both fascicle disarray and myocardial fibrosis were predominant in the septal portion of the anterior and posterior walls,14 in which reverse redistribution of Tc-99m-tetrofosmin was frequently detected in the present study. Therefore, reverse redistribution of Tc-99m-tet-rofosmin in patients with hypertrophic cardiomyopathy may be related to myocardial architectural abnormalities. Regarding the mechanism of the uptake of Tc-99m-tetrofosmin by myocytes, Younes et al. reported that Tc-99m-tetrofosmin accumulation by the mitochondria of myocytes is related to the ability of this tracer to transduce metabolic energy into electron-negative membrane po-tential, 19,20 Considering this experimental result, we speculated that in patients with hypertrophic cardiomyopathy the ability of this tracer to transduce metabolic energy into membrane potential is impaired for some undefined reasons, causing the relatively rapid clearance of Tc-99m-tetrofosmin from the septal portion of the anterior and posterior walls and the septum. The detection of reverse redistribution by early and delayed Tc-99m-tetrofosmin SPECT after a single injection may provide useful information regarding metabolism in myocytes. Furthermore, as we previously mentioned,21 I-123-b-methyl-p-iodo-phenyl-pentadecanoic acid (I-123-BMIPP) myocardial SPECT in hypertrophic cardiomyopathy often shows defects in the anterior and posterior junctional segments and septum in which reverse redistribution of Tc-99m-tetrofosmin was frequently observed. Therefore, it was suggested that the mechanism of reverse redistribution of Tc-99m-tetrofosmin may be related to abnormalities of fatty acid metabolism in patients with hypertrophic cardi-omyopathy. To confirm this, it is necessary to investigate the correlation between reverse redistribution of Tc-99m-tetrofosmin SPECT and I-123-BMIPP SPECT abnormalities in the same patients. 
Study limitation We determined myocardial uptake of the tracer by visual inspection. To verify our visual impression of the reverse redistribution, it may be necessary to calculate the regional washout rate of Tc-99m-tetrofosmin in EX-30 and EX-180 in patients with hypertrophic cardiomyopathy and control subjects. In the present study, images obtained 30 and 180 minutes after exercise were compared, but it is necessary to investigate whether or not similar findings are found in early and delayed images at rest. 
CONCLUSIONS 
Exercise/rest Tc-99m-tetrofosmin myocardial imaging was a useful method for assessing myocardial perfusion abnormalities in patients with hypertrophic cardiomyopathy. Reverse redistribution was detected at high frequency in early and delayed images of exercise. We assumed that reverse redistribution may reflect a retention disorder of Tc-99m-tetrofosmin caused by some metabolic dysfunction of myocytes. 
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