Impact of exercise rehabilitation on cardiac neuronal function in heart failure: an iodine-123 metaiodobenzylguanidine scintigraphy study

Exercise training can induce important haemodynamic and metabolic adaptations in patients with chronic heart failure due to severe left ventricular dysfunction. This study examined the impact of exercise rehabilitation on cardiac neuronal function using iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy. Fourteen patients (11 men, 3 women; mean age 48 years; range: 36–66 years) with stable chronic heart failure of NYHA class II–III and an initial resting radionuclide left ventricular ejection fraction (LVEF) <50% were enrolled in the study. Patients underwent progressive, supervised endurance training (treadmill test, Bruce protocol) during a 6-month period (60 sessions, 3 sessions per week) at a cardiac rehabilitation referral centre in order to measure exercise parameters. Planar ¹²³I-MIBG scintigraphy provided measurements of cardiac neuronal uptake (heart-mediastinum ratio activity, 4 h after intravenous injection of 185 MBq of MIBG). Radionuclide LVEF was also assessed at the outset and after 6 months of exercise training. Workload (801±428 vs 1229±245 kpm·min^–1, P = 0.001), exercise duration (504±190 vs 649±125 s, P = 0.02), and myocardial MIBG uptake (135%±19% vs 156%±25%, P = 0.02) increased significantly after rehabilitation. However, LVEF did not change significantly (23%±9% vs 21%±10%, p = NS). It is concluded that exercise rehabilitation induces improvement of cardiac neuronal function without having negative effects on cardiac contractility in patients with stable chronic heart failure. Received 23 September and in revised form 24 November 1997     

Detection of abnormal cardiac adrenergic neuron activity in adriamycin-induced cardiomyopathy with iodine-125-metaiodobenzylguanidine.

Radiolabeled metaiodobenzylguanidine (MIBG), an analog of norepinephrine (NE), serves as an index of adrenergic neuron integrity and function. Using a rat model of adriamycin-induced cardiomyopathy, we tested the hypothesis that abnormal cardiac adrenergic neuron activity may appear and be exacerbated dose-dependently in adriamycin cardiomyopathy. The degree of vacuolar degeneration of myocardial cells was analyzed in relation to the duration of adriamycin treatment (2 mg/kg, once a week). There were no abnormalities or only isolated degeneration in the 1- or 2-wk treatment groups, isolated or scattered degeneration in half of the 3-wk group, frequent scattered degeneration in the 4-wk group, scattered or focal degeneration in the 5-wk group, and extensive degeneration in the 8-wk group. Myocardial accumulation of [125I]MIBG 4 hr after intravenous injection did not differ between the controls and the groups treated 3 wk or less. However, the 4-wk group had a slightly lower accumulation in the right ventricular wall (82% of the control) and significantly lower accumulation in the left ventricular wall (about 66% of the control: p less than 0.05). In the 5-wk group, MIBG accumulation in the right and left ventricular wall was 35% and 27% of that in controls, respectively (p less than 0.001). In the 8-wk group, MIBG accumulation in the right and left ventricular wall was 18% and 14% of that in controls, respectively (p less than 0.001). Thus, MIBG accumulation in the myocardium decreased in an adriamycin dose-dependent manner. The appearance of impaired cardiac adrenergic neuron activity in the presence of slight myocardial impairment (scattered or focal vacuolar degeneration) indicates that MIBG scintigraphy may be a useful method for detection of adriamycin-induced cardiomyopathy.     

Three-dimensional coronary angiography of the perfused rat heart

The purpose of this work was to visualize the whole three-dimensional coronary artery tree of the perfused beating rat heart using three-dimensional MRI. The spatial resolution amounts to 140 μm. Also, vessels having smaller diameters could be detected. Different strategies for the visualization of the three-dimensional coronary angiograms including maximum intensity projection, data thresholding, and segmentation, were shown. The coronary artery tree was best visualized by hysteresis threshold segmentation and subsequent surface reconstruction.     

131I-metaiodobenzylguanidine uptake in the isolated rat lung: A potential marker of endothelial cell function

The pulmonary vascular endothelial cell plays an important role in the uptake of circulating biogenic amines. In cultured adrenomedullary cells, metaiodobenzylguanidine (MIBG) and norepinephrine (NE) are taken up by the same sodium-dependent active transport system. To examine whether a similar process occurs in the lung, the mechanism of single pass ¹³¹I-MIBG accumulation was studied in rat lungs perfused with a Krebs-Ringer bicarbonate buffer containing 4.5% bovine albumin. MIBG lung accumulation was measured as the percent extraction per g of lung tissue. In control experiments the extraction was 19.7±2.3%/g (n=38) using a perfusate containing 0.01 M MIBG. MIBG accumulation was significantly depressed (% decrease from control) by: cold media at 4° C (84%), 0.5 mM ouabain (67%), 10 M imipramine (70%), 0.7 M serotonin (22%) and 40 mM K⁺ (48%). Pulmonary uptake of MIBG was characterized by Michaelis-Menten kinetics (K _m=0.92×10^-6 M and V _max=2.09×10^-9 moles/g per min). The addition of NE (0.5 M) also altered MIBG uptake such that the K _m and V _max became 0.52×10^-6 M and 0.93×10^-9 moles/g per min, respectively. The results indicate that MIBG accumulation in the lung involves sodium-dependent, energy-requiring, active transport mechanisms similar to those known to exist for norepinephrine, and suggest that MIBG may be useful as a marker of pulmonary endothelial cell function.     

Radiation effects of iodine-125 and iodine-131 on the overactive rat thyroid.

The effects of graded doses of iodine-125 and iodine-131 on rat thyroid glands under prolonged stimulation with oral thyrotropin-releasing hormone were assessed by histological and autoradiographic studies. No evidence for a difference in effect between iodine-125 and iodine-131 was found. The reason for this is suggested.     

Thyroid uptake of MIBG in Sipple's syndrome

The use of the adrenomedullary tracer metaiodobenzylguanidine (MIBG) in the localization of medullary carcinoma of the thyroid (MCT) is based on the embryologic relationship of the APUD cell series. The authors report the results obtained in six patients with MCT: two had Sipple's syndrome and four sporadic forms of the disease. MIBG uptake by the CMT was observed in both cases of Sipple's syndrome and in only one of the other cases. Scintigraphic detection seems to depend on the clinical features, the size of the tumour and also on the part played by its secretory function. MCT would thus appear to be more frequently visualized by MIBG in cases of Sipple's syndrome than in sporadic cases. The procedure therefore seems useful in the diagnosis, follow up and even in the treatment of MCT.     

Value of iodine-123 metaiodobenzylguanidine scintigraphy in patients with vasospastic angina

To assess the presence and location of presynaptic myocardial sympathetic abnormality in patients with vasospastic angina, iodine-123 labelled metaiodobenzylguanidine (MIBG) single-photon emission tomography (SPET) was performed. Fifty patients suspected of having vasospastic angina pectoris were enrolled in the study. All patients underwent a provocative test with intracoronary ergonovine infusion during coronary angiography, in which 99%–100% obstructive spasm was defined as a positive result. Twenty-five patients were diagnosed as having vasospastic angina based on a positive provocative test. MIBG SPET was performed at 20 min and 3 h after administration of 111 MBq of MIBG. On early images, only 5 of 25 patients with vasospastic angina showed a mild reduction in MIBG uptake, whereas 3-h delayed images demonstrated MIBG abnormality in 20 patients (80%). The location of the MIBG abnormality was completely or partially consistent with the spastic coronary territory in 18 patients. On the other hand, only 4 of 25 patients (16%) with a negative provocative test demonstrated reduced MIBG uptake. Accordingly, positive and negative predictive values of MIBG SPET for the provocative test were 83% (20/24) and 81% (21/26) respectively. In conclusion, MIBG scintigraphy with SPET can permit the non-invasive detection and evaluation of suspected vasospastic angina. Received 16 July and in revised form 26 November 1997     

Cardiac sympathetic denervation in familial amyloid polyneuropathy assessed by iodine-123 metaiodobenzylguanidine scintigraphy and heart rate variability

Familial amyloid polyneuropathy (FAP) is a rare and severe hereditary form of amyloidosis, due to nervous deposits of a genetic variant transthyretin produced by the liver and characterized by both sensorimotor and autonomic neuropathy. Left ventricular systolic dysfunction is rare, but conduction disturbances and sudden deaths can occur. The neurological status of the heart has not been elucidated, and an alteration of the sympathetic nerves may be involved. We studied 17 patients (42±12 years) before liver transplantation by iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy, heart rate variability analysis, coronary angiography, radionuclide ventriculography, rest thallium single-photon emission tomography (SPET) and echocardiography. Coronary arteries, left ventricular systolic function and rest thallium SPET were normal in all patients. Only mild evidence of amyloid infiltration was found at echocardiographic examination. Cardiac MIBG uptake was dramatically decreased in patients compared with age-matched control subjects (heart-to-mediastinum activity ratio at 4 h: 1.36±0.26 versus 1.98±0.35, P<0.001), while there was no difference in MIBG washout rate. Heart rate variability analysis showed a considerable scatter of values, with high values in four patients despite cardiac sympathetic denervation as assessed by MIBG imaging. The clinical severity of the polyneuropathy correlated with MIBG uptake at 4 h but not with the heart rate variability indices. Cardiac MIBG uptake and the heart rate variability indices did not differ according to the presence or absence of conduction disturbances. Patients with FAP have sympathetic cardiac denervation as assessed by MIBG imaging despite a preserved left ventricular systolic function and cardiac perfusion, without correlation with conduction disturbances. Results of the heart rate variability analysis were more variable and this technique does not seem to be the best way to evaluate the extent of cardiac sympathetic denervation in FAP patients. Received 19 October 1998 and in revised form 6 January 1999     

Glucose consumption and methionine uptake in low-grade gliomas after iodine-125 brachytherapy

We investigated whether 2-[¹⁸F]-fluoro-2-de-oxy-d-glucose (FDG) and carbon-11 methionine are suitable tracers to monitor the effects of therapy for low-grade gliomas. Ten patients with low-grade glioma without previous treatment were studied with FDG positron emission tomography. Additionally,l-[methyl-¹¹C]-methionine uptake was measured in five subjects before and 1 year after computerized tomography (CT)-guided stereotactic and computer-assisted implantation of iodine-125 seeds. All scans were 3D-matched to CT, isodose volumes were determined, and changes in glucose metabolism and methionine uptake were evaluated in tumour and brain tissue as a function of radiation dose. After 1 year glucose metabolism was not significantly altered up to a radiation dose of 300 Gy, whereas methionine uptake showed a significant dose-dependent decrease. Higher rates of decline were found in tumours with high basal methionine incorporation activity before therapy. These data suggest that measurement of methionine uptake is more suitable than measurement of FDG uptake for monitoring therapeutic effects in low-grade gliomas.     

Lung uptake of 131I-metaiodobenzylguanidine in sheep

Circulating biogenic amines are known to be cleared by the mammalian lung. Their lung uptake is considered as an indicator of pulmonary endothelial integrity. Unfortunately, their use as markers of pulmonary metabolic function in human pathology is precluded by their biological effects and by the type of radiolabeling (³H and ¹⁴C), making them harmful for repeat injections and unfit for scintigraphy. Metaiodobenzylguanidine (MIBG) is structurally related to the neuron blocking agent guanethidine, devoid of significant biological effects, and has been shown to be extracted by the same active sodium dependent, saturable transport as norepinephrine in perfused rat lungs in vitro. We studied the single pass lung extraction of ¹³¹I-MIBG in five awake and five anaesthetised sheep using the standard double indicator dilution technique with ^99mTc-human serum albumin (HSA) as an intravascular reference tracer. Intravenous bolus injection of increasing doses of MIBG up to 400 nmol resulted in a significant (F ratio=7.778, P<0.0001) dose dependent decrease of MIBG extraction in both awake and anaesthetised sheep, without significant differences of extraction values between the two groups. For the 10 sheep, the averaged percentage single pass pulmonary uptake of MIBG at the peak of the dilution curve decreased from 32%±3% (mean±SE, n=27 measurements) with 20 nmol to 18%±2% (n=32) with 400 nmol. Estimates of the apparent Michaelis-Menten constant (K _m) averaged 2±1.2 M (n=7), whereas estimates of the apparent maximum velocity of removal (V _max) was 1.1±0.5 mol/min (n=7). In contrast to some intersubject variability, the pharmacokinetic parameters showed little intra subject variation. No correlation was found between MIBG extraction, K _m or V _max values and haemodynamic or gas exchange parameters. These data indicate that using a standard double dilution technique, lung extraction of MIBG may be determined in vivo. Its lung removal is dose limited and may be characterised by the Michaelis-Menten kinetic constants suggesting a saturable process. In contrast to norepinephrine, the gamma emitter labeled MIBG could therefore be a suitable compound to monitor pulmonary endothelial cell function in vivo using a non invasive scintigraphic method.Supported by the Swiss National Fundation for Scientific Research under contract No 3.985-0.86     

大鼠颈部异位心脏移植模型的建立与超声心动图观察

目的:探讨高频超声心动图观察大鼠颈部异位心脏移植模型的可行性及观察方法。方法:23例大鼠建立颈部异位心脏移植模型,其中同系移植6例,同种移植17例。术前对原位心脏行超声心动图观察,常规记录原位心左室长轴切面、乳头肌水平左室短轴切面、心底短轴切面及心尖四腔切面,测量舒张末期、收缩末期左室内径、舒张末期左室壁厚度、左室射血分数。术后立即对移植心脏行超声心动图观察,并显示上述切面,测量相应超声指标,所测指标与术前原位心比较。结果:23只实验鼠原位心可显示乳头肌水平短轴、心底短轴、左室长轴和心尖四腔切面各为19例、11例、10例和9例;异位移植心与原位心比较,移植心左室短轴内径明显减小;左室射血分数明显减低。结论:大鼠颈部异位心脏移植模型与原位心和腹腔异位移植心脏相比较乳头肌水平左室短轴切面是评价移植心脏形态、大小与心肌功能改变较为理想的切面。     

超声心动图评价大鼠异位移植心脏急性排斥反应的初步实验研究

目的:探讨高频超声心动图评价大鼠颈部异位移植心脏的急性排斥反应的价值。方法:采用高频超声心动图测量17只同种异体移植及6只同系移植心脏测量左室内径、心肌厚度、左室重量和心功能等。6只同系移植大鼠和9只同种异体移植大鼠,分别于移植术后第1、3、5天,采用高频超声对上述指标进行测量,第五天测量完毕后处死并做病理检查。另8只同种异体移植心脏,分别于移植术后第1、3天各测量一次,第3天测量完毕后处死做病理学检查,超声指标与病理结果相对照。结果:①同种异体移植术后,随着移植时间的延长,左室心肌厚度和左室重量逐渐增加,左室内径减小,射血分数无显著性改变;②术后第3天,组织学检查表明已有排斥反应发生,超声检查显示室壁厚度与左室重量明显增加,而常规心脏触诊未能及时发现排斥反应;③随着组织学分级加重显示的排斥,左室心肌厚度与左室重量有显著的增加。结论:室壁厚度和左室重量为超声评价排斥反应发生的敏感、准确指标。高频超声为心脏移植实验研究评价排斥反应提供了一种较为简便可靠的观察方法,为临床上心脏移植的排斥反应的超声评价提供了依据。     

Diagnosis and follow-up of neuroblastoma by means of iodine-123 metaiodobenzylguanidine scintigraphy and bone scan,and the influence of histology

The purpose of this work was to compare technetium-99m-diphosphono-propanedicarboxylate (DPD) and iodine- 123-metaiodobenzylguanidine (MIBG) scans in the diagnosis and follow-up of neuroblastoma, and to study the role of histological differentiation in the uptake of MIBG. The uptake of MIBG and of DPD were studied retrospectively in 27 patients with neuroblastoma (primary, residual and recurrent tumours as well as bone and bone marrow metastases). The findings were related to the histological classification of the tumours as neuroblastoma (N1), differentiating neuroblastoma (N2) or ganglioneuroblastoma (N3). Uptake of MIBG by the primary tumour occurred in 17 of 19 patients, either at diagnosis or during follow-up. There were only two false-negatives with MIBG, both of which were N3. Ten patients were studied preoperatively with both MIBG and DPD. The primary tumour showed MIBG uptake in nine of the ten and DPD uptake in eight of them. Thirty-five sites of cortical bone metastasis were shown in eight patients by both MIBG and DPD, 12 sites in seven patients by MIBG only and seven sites in five patients by DPD only. In 14 patients both MIBG and bone scan were negative. Overall, MIBG demonstrated more lesions than DPD. Retrospectively several hot spots seen only with the bone scan are to be considered as false-positive. The highest incidence of false-negative MIBG and bone scans was observed in ganglioneuroblastoma with a predominance of the more mature component (ganglioneuroma).     

Differences in the intracellular processing of the radiolabel following the uptake of iodine-125- and technetium-99m-neogalactosyl albumin by the isolated perfused rat liver

Neogalactosyl albumin (NGA) is a synthetic ligand to the asialoglycoprotein receptor (hepatic binding protein), which has been proposed as a useful receptor binding radiopharmaceutical for the noninvasive assessment of liver function. We have compared the uptake and intracellular processing of iodine-125- (125I) and technetium-99m- (99mTc) NGA following its administration as a 1-min pulse (147 pmol) to the isolated perfused rat liver. Approximately 40% of a pulse of either 125I- or 99mTc-NGA were taken up first pass by the liver. Of the 125I taken up by the liver, 82% was released after 15-20 min at the sinusoidal pole of the hepatocyte, predominantly as small molecular weight metabolites. A further 8% of the 125I-associated radioactivity was secreted as intact NGA into bile by the non-lysosomal (direct) pathway while 6% remained in the liver 1 hr after the pulse. In contrast, of the 99mTc taken up by the liver, only 4% reappeared in the perfusate while 40% was secreted into bile by the lysosomal (indirect) pathway and 55% remained in the liver 1 hr after the pulse. Since labeled metabolites of 99mTc-NGA do not appear in plasma, this permits kinetic modeling with 99mTc-NGA without correction for labeled metabolites. Thus, 99mTc-NGA is an excellent candidate as a receptor-binding radiopharmaceutical.     

Activity of iodine-123 metaiodobenzylguanidine in childhood neuroblastoma: lack of relation to tumour differentiation in vivo

Neuroblastoma (NB) tumour cells have a remarkable tendency to differentiate spontaneously or under the influence of certain drugs. It is not clear whether metaiodobenzylguanidine (MIBG) uptake correlates with differentiation of NB cells. In 28 tumours of 26 patients, iodine-123 MIBG uptake in primary NBs was studied in relation to tumour differentiation, tumour size, cell density and degree of necrosis in subsequently resected specimens. Genetic features such as the presence of chromosomal aberrations (1p-deletion and MYCN amplification) and/or P-glycoprotein (mdr-1 gene product) were also evaluated in relation to MIBG uptake. A highly variable and unpredictable intensity of MIBG uptake was observed in primary as well as secondary resected tumours. This intensity did not relate to any of the above-mentioned factors except that there was a trend towards more intense uptake with increasing size of the tumour. We conclude from our observations that, in contrast to commonly held opinion, well-differentiated tumours do not a priori show a lower MIBG uptake in vivo, even when there are a low number of viable cells and a high degree of necrosis. The degree of differentiation or tumour viability and necrosis following longstanding chemotherapeutic treatment cannot be predicted by the MIBG scan findings. The observed MIBG uptake may be importantly influenced by factors other than those associated with cellular differentiation. Received 6 August and in revised form 27 September 1997     

Myocardial uptake of meta-[123I]-iodobenzylguanidine ([123I]-MIBG) in patients with myocardial infarct

Meta-¹²³I-iodobenzylguanidine (¹²³I-MIBG), which is an analog of norepinephine, can be used to evaluate the integrity and function of sympathetic nerve endings in the heart. Myocardial uptake of ¹²³I-MIBG was studied in 30 myocardial infarction patients and compared with the distribution of blood flow assessed with ²⁰¹Tl. It was found that when a cold defect appeared on the ²⁰¹Tl scintigram, its localization was identical to the cold defect on the ¹²³I-MIBG scintigram. On the other hand, in three cases, a defect was found on the ¹²³I-MIBG scintigram, corresponding to the electrocardiographic localization of the infarct, whereas the ²⁰¹Tl scintigram was normal. Most strikingly, the present study shows that drugs (antagonists of the adrenergic receptors, calcium antagonists, amiodarone) decrease or even abolish (as in the case of labetalol) myocardial uptake of ¹²³I-MIBG. Consequently, any interpretation of the ¹²³I-MIBG scintigram must take into account the treatment administered.     

Clinical value of lung uptake of iodine-123 metaiodobenzylguanidine (MIBG), a myocardial sympathetic nerve imaging agent, in patients with chronic heart failure

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.     

Potential of iodine-123 metaiodobenzylguanidine single-photon emission tomography to detect abnormal functional status of the pulmonary neuroadrenergic system in irradiated lung

The potential of iodine-123 metaiodobenzylguanidine (MIBG) to detect functional abnormalities of the pulmonary neuroadrenergic system (PNS) in irradiated lung areas (ILAS) was preliminarily explored using single-photon emission tomography (SPET). The subjects included five healthy subjects and a total of 31 patients with peripheral-type lung cancer treated by radiation; 15 patients (group A) had received a dose of less than 36 Gy (mean ± SD: 28.2 ±6.2 Gy), and 16 patients (group B) had received a higher dose (mean ± SD: 51.2 ± 3.5 Gy) at the time of examination. MIBG SPET scans aquired 15 min and 3 h after injection were used to measure the MIBG uptake ratio (count ratio of the ILA to the contralateral non-ILA) and the clearance rate [percentage of (early counts – delayed counts)/early counts] from the ILAs without noticeable abnormal opacities on chest computed tomography scan. Lung perfusion changes were also assessed by technetium-99m macroaggregated albumin SPET. By contrast to the homogeneous MIBG uptake in the lungs of the healthy subjects, MIBG uptake was folcally decreased in correspondence with the ILAs in all patients, including 11 patients (73.3%) of group A with relatively preserved lung perfusion. The reduction MIBG uptake was significant (P<0.0001), and the MIBG clearance rate from the ILAs was also significantly faster than the clearance rates from the normal lungs and contralateral non-ILAs (both P<0.01). Group B patients showed significantly lower MIBG uptake and faster clearance from the ILAs than group A patients (P<0.001 and P<0.05, respectively), although there was no significant difference in the clearance from the non-ILAs. Overall, MIBG uptake/clearance from the ILAs correlated significantly with the radiation dose in the 31 patients (r = –0.656; P<0.0001 and r = 0.387; P<0.05, respectively). Perfusion changes were inversely correlated with the clearance from the ILAs (r = –0.432, P<0.05), but did not correlate with MIBG uptake. These preliminary results suggest that MIBG may have the potential to be a marker of abnormal functional status of the PNS produced by irradiation and may facilitate investigation of irradiation lung injury independently of morphological or lung perfusion changes. Received 11 December 1998 and in revised form 10 February 1999     

The experimental brachytherapy of rhabdomyosarcoma R1H in the rat with iodine-125 seeds]

Rhabdomyosarcoma R1H of the rat with a volume of 1.2 cm3 were treated by implanting three to eight iodine-125 seeds (20.4 MBq). While implantation of inactive seeds had no influence on tumour growth, implantation of three or four seeds caused a reduction in tumour growth rate. Local tumour control was achieved in 71 and 80% of the tumours after implantation of seven and eight seeds, respectively.