ORIGINAL A R T I C L E Annals of Nuclear Medicine Vol. 15, No. 5, 411--416, 2001

Clinical value of lung uptake of iodine-123 metaiodobenzylguanidine (MIBG), a myocardial sympathetic nerve imaging agent, in patients with chronic heart failure Xiuli Mu,* Shinji HASEGAWA,*Jun YOSHIOKA,*Atsushi MARUYAMA,*Kaoru MARUYAMA,* Asit K. PAUL,*Hitoshi YAMAGUCHI,*Takakazu MOROZUMI,**Katsuji HASHIMOTO,*** Hideo KUSUOKA***and Tsunehiko NISH1MURA*

*Division of Tracer Kinetics, Osaka University Graduate School of Medicine **Kansai Rousai Hospital ***Osaka National Hospital

This study investigated the clinical value of I-123 MIBG pulmonary accumulation and washout in patients with chronic heart failure (CHF). Nineteen patients with CHF and 15 normal volunteers (NL) were included. The uptake ratio of heart to mediastinum (H/M), that of lung fields to mediastinum (L/M), and washout rate (WR) of the heart and lung fields were calculated in anterior planar images and compared with results of echocardiography and cardiac catheterization. In the CHF group, the lung uptake in delayed images increased and lung WR was decreased, suggesting pulmonary endothelial lesions. Furthermore, there was a negative correlation between right and left lung WR and pulmonary arterial diastolic pressure (PA(D)) and pulmonary arterial systolic pressure (PA(s)) in the CHF group. Since the WR of MIBG reflected PA, it may be used as an index of severity of cardiac dysfunction.

Key words: iodine-123 MIBG, chronic heart failure, lung uptake

INTRODUCTION METAIODOBENZYLGUANIDINE(MIBG) is an analog of the adrenergic neuron-blocking agent guanethidine, and shares the same uptake, storage and release mechanisms as norepinephrine (NE) in sympathetic nerve endings. 1-5 Because the myocardium is richly supplied with sympathetic nerves, myocardial imaging with 1-123 MIBG has been used to assess cardiac sympathetic nervous activity6-11; myocardial uptake of MIBG was decreased and myocardial washout of MIBG was increased in heart failure, l~ On the other hand, abnormal MIBG kinetics in the patients with diabetic mellitus leA3 and chronic hypoxia in the lung 14 has been reported. It has been also reported that sympathetic nerve dysfunction changes the Received February 15, 2001, revision accepted June 4, 2001. For reprint contact: Tsunehiko Nishimura, M.D., Division of Tracer Kinetics (D9), Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita 565-0871, JAPAN. E-mail: [email protected]

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MIBG kinetics in the lung, 12.13 but pulmonary 1-123 MIBG kinetics in chronic heart failure (CHF) has not been clarified. In this study, we investigated pulmonary kinetics of 1-123 MIBG in patients with CHF.

MATERIALS AND METHODS Thirty-four subjects, including 19 patients with CHF, and 15 normal volunteers were examined. The CHF group consisted of 14 dilated cardiomyopathy (DCM) patients and 5 ischemic heart disease (IHD) patients. The CHF group included 16 men and 3 women, with a mean age of 50 + 16 years (mean + SD). The normal group included 15 men, with a mean age of 33 + 10 years. Because all in the normal group were volunteers, there was no matching of age with patients. The diagnosis of DCM or IHD was based on the finding of echocardiography and cardiac catheterization. DCM patients showed no significant coronary artery stenosis detected by coronary angiography, and the findings of biopsies such as myocyte hypertrophy and fibrosis. IHD patients had old myocardial infarction.

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All of them had a low left ventricular ejection fraction (LVEF) less than 40% evaluated by echocardiography (27.10 + 7.40%).

where H, M, rtL and ltL represent the counts at the heart, mediastinum, right lung and left lung, and 1 and 2 indicate early image and delayed image, respectively.

Imaging with 1-123 MIBG The 1-123 MIBG imaging was performed as reported previouslyJ 5 Briefly, 111 MBq of I- 123 MIBG (Daiichi Radioisotope Laboratories, Tokyo, Japan) was injected intravenously at resting and fasting. Anterior planar images were obtained over 5 min at 15 min and 240 min after the injection. Imaging was performed with a triple-headed gamma camera equipped with a low-energy generalpurpose collimator (TOSHIBA GCA-9300A/HG, Tokyo, Japan), and data were processed with an imaging processing system (TOSHIBA GMS-5500U, Tokyo, Japan). As shown in Figure 1, regions of interest (ROIs) were placed over the heart, superior mediastinum, upper right lung and upper left lung. Based on the average counts per pixel in each ROI, the accumulation ratio of heart to mediastinum (early images: H1/M1, delayed images: H2/ M2), right lung to mediastinum (early images: rtL1/M1, delayed images: rtL2/M2) and left lung to mediastinum (early images: ltL 1/M 1, delayed images: ItL2/M2) were calculated at 15 min (early images) and 240 min (delayed images), respectively. MIBG WR between early and delayed images of heart (WR-H (%)), right lung (WR-rtL (%)) and left lung (WR-ltL (%)) were also calculated as follows;

Measurement of cardiac function Left ventricular end-diastolic diameter (LVDd) and endsystolic diameter (LVDs) were measured by M-mode echocardiography at the level of the mitral tendinous cord. The left ventricular ejection fraction (LVEF) was calculated by the Teichholtz Method.16 The following data were obtained by cardiac catheterization; pulmonary arterial diastolic (PA(o)), systolic (PA(s)) and mean pressure (PA(m)), mean wedge pressure (PCWP), right atrial pressure (RA), cardiac index (CI), left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP). The evaluation of cardiac function was performed within one month before or after the MIBG imaging.

WR-H (%) WR-rtL (%)

-

(HI

(rtL1

Statistical analysis Data are expressed as the mean + S.D. An unpaired t-test was used for the comparison between two groups. P value less than 0.05 was considered to be statistically significant. RESULTS As summarized in Table 1, the LV dimension was greater and EF was smaller in DCM patients, but there were no significant difference between DCM and IHD groups in hemodynamic indexes. The normal range of each index was picked up from the reference) 7 Figure 1 demonstrates representative MIBG images in the patient with CHF due to DCM. In this case, echocardiography showed diffuse hypokinesis of the left ventricular wall, dilation of the left ventricle (LVDd: 78 mm, LVDs: 65 mm) with low EF (34%) and severe mitral regurgitation. PA pressure was increased (51/15 (29)

M1) - (H2 - M2) x 100 (H1 - M 1 )

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(nL1 - M1)

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100

WR-ltL (%) = (ltL1 - MI) - (ltL2 - M2) x l 0 0 (ltL1 - M1)

Table 1 Indexes obtained by echocardiography and catheterization in DCM and IHD patients, and the normal range of each indexes. Normal range* n

LVDd (mm) LVDs (mm) EF (%) PA(s) (mmHg) PA(D) (mmHg) PA(m) (mmHg) PCWP (mmHg) RA(m) (mmHg) CI (Umin/m2) LVSP (mmHg) LVEDP (mmHg)

40-55 30-45 50-80 7-32 4-12 9-19 4-12 2-12 2.5-4 90-140 5-12

DCM 14 66.3• 58.8• 24.6• 25.2• 9.8• 14.1• 10.5• 3.7• 2.74• 120.6• 13.2•

IHD 5 54.8• 43.0• 32.2• 32.0• 11.4• 17.4• 12.8• 7.0• 2.70• 142.2• 14.8•

P value (DCM vs. IHD) <0.05 <0.~1 <0.05 NS NS NS NS NS NS NS NS

* Citation places from reference 17.

412 Xiuli Mu, Shinji Hasegawa, Jun Yoshioka, et al

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(c) Fig. 1 I-123 MIBG myocardial planar images (left: early image, right: delayed image) in a patient with dilated cardiomyopathy (48 years old make). The early image shows clear uptake in the both lungs and inhomogeneous, reduced uptake in the dilated left ventricle. Delayed image indicates decreased washout of both lung and increased washout of the heart. Regions of interest (ROIs) were set over the heart (1), upper mediastinum (2), right lung (3) and left lung (4).

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Fig. 3 Relationships between indexes of 1-123 MIBG images and PA pressure in CHF patients. Closed circle and open circle represent the data of DCM and IHD patients, respectively. PA(s): systolic PA pressure, PA(D): diastolic PA pressure

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Fig. 2 The uptake ratio of lung (L/M) or heart (H/M) to mediastinum and washout rate (WR) of the lung or heart of the 1-123 MIBG images in normal volunteers (NL: open bars) and patients with CHF (closed bars).

mmHg), and PCWP and LVEDP were 24 m m H g and 16 mmHg, respectively. 1-123 M I B G myocardial imaging showed dilation of the left ventricle, and reduced and irregular accumulation. In contrast with decreased myocardial accumulation, pulmonary accumulation was clearly increased. H/M in early and delayed images were 1.81 and 1.71, respectively; both were reduced, and W R - H increased to 41.7%. In contrast, L/M of the right and left lung fields (2.67 and 2.31) in early images were increased, and those of right and left lung fields (2.81 and 2.50) in delayed images were also increased. W R - ~ L and WR-ltL decreased to 27.95% and 24.10%.

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The lung and heart uptake ratio and washout rate of MIBG in patients with CHF are shown in Figure 2. At 4hr after the injection of the tracer, ~L2/M2 (2.13 + 0.33 vs. 1.87 + 0.35, p < 0.05) and ItL2/M2 (1.92 + 0.28 vs. 1.64 + 0.23, p < 0.01) in the CHF group significantly increased when compared with the normal. WR-rtL (52.97 + 13.84 vs. 62.66 + 11.72, p < 0.05) and WR-ltL (53.93 + 13.07 vs. 63.72 + 10.99, p < 0.05) in CHF group significantly decreased. In contrast, the CHF group showed significant decrease in myocardial uptake HI/M1 (2.17 + 0.45 vs. 2.45 + 0.26, p < 0.05) and H2/M2 (2.11 + 0.46 vs. 2.87 + 0.42, p < 0.0001) whereas WR-H (43.08 + 8.70 vs. 26.35 + 9.63, p < 0.0001) was significantly increased. In the normal group, rtL1/M1 showed significant correlation with H1/M1 (r = 0.820, p < 0.0001) and H2/M2 (r = 0.587, p < 0.05), ItL1/M1 correlated with HI/M1 (r = 0.668, p < 0.01) and H2/M2 (r = 0.561, p < 0.05), rtL2/M2 with HI/M1 (r = 0.686, p < 0.01) and H2/M2 (r = 0.589, p < 0.05), and ItL2/M2 with H1/M1 (r = 0.698, p < 0.01) and H2/M2 (r = 0.603, p < 0.05). In the CHF group, rtL1/ M1 correlated significantly with H1/M1 (r = 0.611, p < 0.01) and H2/M2 (r = 0.521, p < 0.05), and ltL1/M1 correlated with H1/M1 (r = 0.642, p < 0.01) and H2/M2 (r = 0.507, p < 0.05).

Relationship between pulmonary indexes of MIBG and cardiac function The relationship between pulmonary indexes of 1-123 MIBG scintigraphy and PA pressure is shown in Figure 3. In whole CHF patients, there were significant negative correlations between WR-rtL and PA(s) (Fig. 3a), and PA(D) (Fig. 3c), and between WR-ltL and PA(s) (Fig. 3b),

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and PA(o) (Fig. 3d). In addition, when only DCM patients were picked up, a similar significant negative correlation was observed between WR-rtL and PA(s) (Fig. 3a, r = -0.54, p < 0.05), and PA(o) (Fig. 3c, r = -0.59, p < 0.05), and between WRitL and PA(s) (Fig. 3b, r =-0.64, p < 0.05), and PA(D) (Fig. 3d, r = -0.61, p < 0.05). When only IHD patients were picked up, a similar significant negative correlation was observed between WR-rtL and PA(s) (Fig. 3a, r = -0.933, p < 0.05) and PA(D) (Fig. 3c, r = -0.901, p < 0.05), and between WR-ItL and PA(s) (Fig. 3b, r = -0.934, p < 0.05) and PA(D) (Fig. 3d, r = -0.935, p < 0.05), but no significant differences between pulmonary indexes of MIBG and other indexes of cardiac function were observed. DISCUSSION Our results showed that myocardial uptake of MIBG decreased and the myocardial washout rate of MIBG increased in the patients with CHF, which was consistent with previous reports. 1s-2~This phenomenon has been considered to be caused by myocardial sympathetic nerve dysfunction. In contrast with myocardial MIBG images, pulmonary MIBG images showed no difference in early images, but presented increased uptake in delayed images with a decreased washout rate of MIBG when comparing CHF group with the normal volunteers. In addition, there was a negative correlation between the lung washout rate of MIBG and PA(s) or PA(D). These results suggest that the abnormal kinetics of MIBG is associated with abnormal function of pulmonary endothelial cells and sclerosis of the pulmonary vasculature. The lung actively takes up 1-123 MIBG through a saturable, energy-requiring, sodium-dependent transport mechanism similar to biogenic amines. 21-24Previous studies confirmed the diagnostic value of MIBG as an excellent marker of minimal endothelial cell lesions. 14.21-25 It is known that transport of biogenic amines requires normal endothelial cell integrity. In the lung toxicity of bleomycin and chronic exposure to hypoxia, decreased pulmonary retention of I-123 MIBG has been noted and attributed to intracytoplasmic edema and endothelial blebbing, both detected by electron microscopy. 14,25 Richalet et al. 14demonstrated a decrease in 1-123 MIBG extraction by the lung in chronic hypoxia and has been attributed to the changes in pulmonary circulation involving an alteration of either the vascular surface area or endothelial cell function. On the other hand, Unlu et al. 12 reported prolonged MIBG retention in diabetic patients with coronary artery disease, which may possibly be due to thickening of the capillary basal membrane. In our study, increased uptake of MIBG and decreased washout rate of MIBG in lungs in patients with CHF was shown. Chronic heart failure might lead to a change in pulmonary circulation, and the thickening and sclerosis of the pulmo-

414 Xiuli Mu, Shinji Hasegawa, Jun Yoshioka, et al

nary vasculature, which causes a delay in the clearance of this compound rather than any abnormality in uptake. In previous reportsY '26 Tc-99m-human serum albumin and T1-201 were used to differentiate 1-123 MIBG lung uptake from residual nonspecific lung activity and passive pooling. These results supported the concept that 1-123 MIBG accumulated in the lungs through a specific mechanism, different from T1-201 and Tc-99m-human serum albumin. The increased pulmonary capillary wedge pressure, which has been demonstrated to be correlated with an increase in lung thallium activity27,28in the resting phase, may damage the pulmonary endothelium, but the effect of CHF on pulmonary endothelium and its clinical importance remains to be elucidated. Glowniak et al. l~ and Dae et al.I i reported that the lung uptake of I- 123 MIBG was increased in patients with DCM. They suggested that increased MIBG uptake in the lungs might result from pulmonary hypertension in those patients, since increased NE extraction by the lungs from the blood was observed in patients with pulmonary hypertension. Lung uptake of biogenic amine is even higher when pulmonary artery pressure is high, 29 and the increased uptake of MIBG in transplant patients (in whom pulmonary artery pressure was very high immediately prior to transplant) was reported. 10On the other hand, no significant difference between DCM patients and healthy subjects in the lung uptake of I-123 MIBG was reported, 13 but there is no information as to whether those patients also had higher pulmonary artery pressure. In our study, a negative correlation between the lung washout rate of MIBG and PA(s) and PA(o) was observed. These results suggest that the lung kinetics of MIBG was associated with pulmonary artery pressure as previously indicated. In other words, the results were suggestive of the progress of pulmonary endothelial dysfunction in CHF patients. The higher pulmonary artery pressure with CHF more easily leads to a change in pulmonary circulation, resulting in abnormal function of pulmonary endothelial cells, and increased lung uptake and decreased lung washout rate of MIBG. Even when DCM or IHD patients were separately picked up, a negative correlation between the lung washout rate of MIBG and PA(s) or PA(D) was observed. In the IHD group, LVEF was significantly higher and LVDd and LVDs were lower than in the DCM group, but no significant differences were observed between the IHD and DCM groups in pulmonary artery pressure or indexes of MIBG. These results suggest that a similar obstacle exists in pulmonary endothelial cells oflHD and DCM patients. In other words, in the IHD group, even if LVEF does not fall very much, heart failure may be equal in severity, and PA and PCWP are also very important as indexes of heart failure. LVEF may underestimate the severity of heart failure in IHD patients. In normal groups, there was a positive significant correlation between the both lung uptake rate and the heart uptake rate in early and delayed images. In the CHF

Annals of Nuclear Medicine

group, there were positive significant correlations between both lung uptake and the heart uptake rate in early images, but no correlation in delayed images. Theses results were not consistent with a previous reportJ I This could be caused by the fact that the uptake at the mediastinum has to greatly affects H/M and L/M. In our study the abnormal function of pulmonary endothelial cells may possibly be due to the sclerosis of the pulmonary vasculature and the thickening of the capillary basal membrane. Especially hypoxia in CHF with the higher pulmonary artery pressure may cause spasms of the fine arterioles, and enhance the permeability of the pulmonary endothelial cells. The concentration of circulating hormones is unusually high in patients with pulmonary hypertension, and it was reported that in perfused guinea pig lung angiotensin enhances NE uptake, and this may also occur in man. 3~Therefore, the lung could take up 1-123 MIBG which is an analog of NE. Increased lung uptake of MIBG may be due to the enhanced permeability of the pulmonary endothelial cells, and the decreased lung washout rate of MIBG may be due to the thickening of the capillary basal membrane. Smooth muscles, mucous glands and blood vessels of the respiratory tract in the lungs are dominated by autonomic nerves. So pulmonary accumulation of MIBG was related not only to the number of pulmonary endothelial cells and the degree of damage of them but also to many other factors such as distribution of sympathetic nerves in the pulmonary blood vessels and bronchus. In order to demonstrate the physiological and pathological significance of pulmonary accumulation of I-123 MIBG, more detailed investigation including a preclinical study may be necessary in the future. CONCLUSION In the patients with CHF, increased lung uptake in delayed images and a decreased lung washout rate of MIBG was observed. Furthermore, the pulmonary washout rate showed a significant correlation with PA pressure, suggesting that the washout rate could be used as an index to assess the severity of pulmonary hypertension in CHF. ACKNOWLEDGMENT A part of the study was supported by Takatsuki Rotary Club (to XM).

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