In vivo evidence of endothelial injury in chronic obstructive pulmonary disease by lung scintigraphic assessment of (123)I-metaiodobenzylguanidine.

Scintigraphic evaluation of (123)I-metaiodobenzylguanidine ((123)I-MIBG) in the lungs is considered to recognize endothelial cell lesions. The aim of this study was to clarify the involvement of the pulmonary microvascular injury in the pathogenesis of chronic obstructive pulmonary disease (COPD). METHODS: We investigated lung (123)I-MIBG kinetics and clinical indices in 25 COPD patients and 12 control subjects. Mean uptake ratios of lung to mediastinum (L/M) were calculated in anterior planer images at 30 min (early image) and 270 min (delayed image) after intravenous injection of (123)I-MIBG. Pulmonary mean washout rate (WR) of the (123)I-MIBG was also calculated. RESULTS: The L/M ratios in both early and delayed images of COPD patients, as well as its WR, were significantly lower than those of the control subjects (L/M early: 1.26 +/- 0.18 vs. 1.54 +/- 0.11, P < 0.0001; L/M delayed: 1.20 +/- 0.12 vs. 1.33 +/- 0.09, P < 0.001; WR: 27.4% +/- 5.3% vs. 34.2% +/- 5.7%, P < 0.01). There were significant relationships between lung WR of the (123)I-MIBG and other diagnostic tests for the severity of COPD, such as forced expiratory volume in 1 s (% FEV(1.0): r = 0.386, P < 0.05), carbon monoxide diffusing capacity/alveolar volume (DL(CO)/V(A): r = 0.449, P < 0.01), arterial blood oxygen pressure (PaO(2): r = 0.474, P < 0.01), alveolar-arterial oxygen tension gradient [A-a]DO(2) (r = -0.446, P < 0.01), and percentage of low-attenuation area (r = -0.458, P < 0.01) in the study population. CONCLUSION: Because lung WR of the (123)I-MIBG is considered to be independent of an alteration of the pulmonary vascular surface area, these results suggest that the microvascular endothelial cell injury plays a significant role in the pathogenesis of COPD.     

123I-MIBG myocardial scintigraphy in patients with "takotsubo" cardiomyopathy.

The clinical characteristics of reversible left ventricular dysfunction due to "takotsubo" cardiomyopathy have been described, but the origin of this condition remains unclear. This study investigated (123)I-metaiodobenzlguanidine ((123)I-MIBG) myocardial scintigraphy in patients with takotsubo cardiomyopathy. METHODS: Eight consecutive patients with takotsubo cardiomyopathy were studied. Left ventricular wall motion was monitored by echocardiography until wall motion normalized. (123)I-MIBG myocardial scintigrams were performed within 3 d of admission (0 mo) and after the improvement of left ventricular dysfunction (3 mo). Early images were obtained at 30 min after radioisotope injection and delayed images were obtained after 4 h. The heart-to-mediastinum ratio (H/M ratio) and the washout rate were calculated. RESULTS: The mean left ventricular ejection fraction improved significantly (from 42.8% +/- 8.7% to 66.5% +/- 7.9%; P < 0.0001) and normalized after 19.4 +/- 5.4 hospital days. The early H/M ratio was significantly higher than the late ratio at 0 mo (2.16 +/- 0.25 vs. 1.89 +/- 0.24, respectively; P < 0.05), but not at 3 mo. The washout rate was significantly greater at 0 mo than at 3 mo (39.1% +/- 10.2% vs. 25.4% +/- 6.3%, respectively; P < 0.05). CONCLUSION: In patients with takotsubo cardiomyopathy, initial (123)I-MIBG myocardial scintigraphy depicted a unique pattern of ventricular asynergy and indicated the existence of cardiac sympathetic hyperactivity, although coronary blood flow was maintained. These findings strongly suggest that takotsubo cardiomyopathy could be caused by neurogenic myocardial stunning.     

Serial change of 123I-metaiodobenzylguanidine (MIBG) myocardial concentration in patients with dilated cardiomyopathy

123I-Metaiodobenzylguanidine (MIBG) is expected to be useful agent for functional evaluation of the myocardial sympathetic innervation. The aim of this paper is to investigate serial change of 123I-MIBG myocardial concentration in patients (pts) with dilated cardiomyopathy (DCM) as compared with 201Tl uptake. Eight pts with DCM and six non-cardiac subjects (controls) were examined. After injection of 111 MBq (3mCi) 201Tl and 111 MBq (3 mCi) 123I-MIBG, simultaneous myocardial imaging in anterior view was performed for both tracers in every 30-60 minutes during 5 hours (6 images). Myocardial uptake ratio per pixel to the injected dose was calculated for each tracer with background and cross-talk correction on each image. In pts with DCM, myocardial uptake ratio of 123I-MIBG did not differ significantly from that of controls. The washout of 123I-MIBG from the myocardium, however, was significantly increased in pts with DCM as compared with controls. The % decrease of the radioactivity in 3 hours was 46.9 +/- 13.8% in DCM, whereas 18.0 +/- 7.7% in controls (p less than 0.05). Especially, the decrease in the early phase (less than 1 hour) was significantly larger in DCM than controls (21.2 +/- 7.5% vs 5.3 +/- 4.0%, p less than 0.01). For 201Tl, on the other hand, neither uptake ratio nor washout rate, differed significantly between the two. In conclusion, the rapid washout of 123I-MIBG in the early phase may reflect some sympathetic dysfunction in pts with DCM.     

Reduced cardiac uptake and enhanced washout of 123I-MIBG in pure autonomic failure occurs conjointly with Parkinson's disease and dementia with Lewy bodies.

The purpose of this study was to investigate myocardial uptake of 123I-metaiodobenzylguanidine (MIBG) in patients with pure autonomic failure (PAF), which has pathologic features in common with idiopathic Parkinson's disease (IPD) and dementia with Lewy bodies (DLB). METHODS: Six patients with PAF, 130 with IPD, 21 with DLB, 9 with corticobasal degeneration (CBD), 11 with progressive supranuclear palsy (PSP), and 11 with multiple-system atrophy (MSA) underwent myocardial 123I-MIBG scintigraphy, as did 16 control patients. RESULTS: Resulting heart-to-mediastinum (H/M) ratios were significantly lower in patients with PAF, IPD, or DLB than in patients with CBD, PSP, or MSA and in the controls. H/M ratios were lower for delayed images than for early ones in patients with PAF, IPD, or DLB, whereas the ratios were higher for delayed images in patients with CBD and in the controls. CONCLUSION: Cardiac sympathetic denervation and enhanced washout of 123I-MIBG from sympathetic nerve terminals may develop in parallel in patients with PAF, IPD, or DLB.     

Serial change of iodine-123 metaiodobenzylguanidine (MIBG) myocardial concentration in patients with dilated cardiomyopathy.

Serial change of the metaiodobenzylguanidine iodine-123 (123I-MIBG) myocardial concentration was investigated in patients with dilated cardiomyopathy (DCM). Eight DCM patients and 6 control subjects were examined. After the injection of thallium-201 and 123I-MIBG, planar chest images were obtained simultaneously for both tracers in every 30-60 min over 5 h. Serial changes of myocardial uptake ratio (MUR) were compared for both tracers. In DCM, the initial MUR of 123I-MIBG did not differ significantly from that of the controls. The washout of 123I-MIBG from the myocardium, however, was significantly increased in DCM. In particular, the decrease in the early phase (15-45 min) was significantly larger in DCM than in the controls (21.2% +/- 7.5% vs. 5.3% +/- 4.0%, P less than 0.01), showing a significant negative correlation with the left ventricular ejection fraction (r = -0.72 P less than 0.05). For 201Tl, neither the initial MUR nor the washout rate different significantly between the two. Thus, an early rapid decrease of the 123I-MIBG myocardial concentration might characterize DCM and reflect the severity of this disease.     

Total and partial cardiac sympathetic denervation after surgical repair of ascending aortic aneurysm.

Sympathetic cardiopulmonary nerves arise from the cervical sympathetic trunks and travel alongside the great arteries to innervate the ventricles. Because of the proximity of the nerve and artery, cardiac sympathetic denervation may occur in patients who have just undergone surgery for the repair of an ascending aortic aneurysm. METHODS: To evaluate the cardiac sympathetic activity in aortic aneurysm, we performed cardiac 123I-metaiodobenzylguanidine (MIBG) imaging on 12 patients (mean age +/- SD, 47 +/- 17 y) before and after the surgical repair of an aneurysm. Seven patients scheduled for coronary artery bypass grafting also underwent 123I-MIBG imaging as controls for open-chest surgery. Planar images were obtained at 15 min (early) and 4 h (delayed) after injection of 111 MBq 123I-MIBG, and the cardiac 123I-MIBG uptake was graded quantitatively and visually. The quantitative evaluation was based on the heart-to-mediastinum ratio (H/M), and visual evaluation was performed by assigning a score of 0-3 (0 = absent, 1 = severely reduced, 2 = reduced, and 3 = normal). Heart rate variability using 24-h Holter electrocardiography was analyzed before and after the operation to generate a time-domain index of heart rate variability as an index of autonomic balance. RESULTS: In patients with aortic aneurysms, both early and delayed H/Ms were significantly decreased after the operation (early H/M: 1.84 +/- 0.16 before vs. 1.40 +/- 0.16 after, P = 0.001; delayed H/M: 1.79 +/- 0.38 before vs. 1.27 +/- 0.18 after, P = 0.004). Visual analysis of 123I-MIBG accumulation in early images showed absence of 123I-MIBG accumulation in 3 of 12 patients, a score of 1 in 7 patients, and a score of 2 in 2 patients. In contrast, no significant difference between H/M before surgery and H/M after surgery was seen in patients who underwent coronary artery bypass grafting. The time-domain index of heart rate variability was significantly lower after the operation than before (135 +/- 40 after vs. 96 +/- 27 before, P < 0.05). CONCLUSION: Cardiac sympathetic nerves are totally or partially denervated after the surgical repair of ascending aortic aneurysm.     

Changes in cardiac sympathetic nerve innervation and activity in pathophysiologic transition from typical to end-stage hypertrophic cardiomyopathy.

Left ventricular (LV) systolic function in hypertrophic cardiomyopathy (HCM) is usually normal. Late in the disease, however, LV systolic dysfunction and dilatation are recognized. Although abnormalities in cardiac sympathetic nerve activity in patients with HCM have been demonstrated using (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, the changes of cardiac sympathetic nerve activity throughout the clinical course from typical to end-stage HCM are unclear. The objective of this study was to evaluate the relationship between abnormalities on (123)I-MIBG myocardial scintigraphy and pathophysiologic changes in patients with HCM. METHODS: We performed (123)I-MIBG scintigraphy on 46 patients with HCM and 18 age-matched control subjects. The patients were categorized into 3 groups: 28 patients with normal LV systolic function (group A), 9 patients with LV systolic dysfunction (group B), and 9 patients with LV systolic dysfunction and dilatation (group C). With planar (123)I-MIBG imaging, the heart-to-mediastinum ratio for early and delayed acquisitions and the washout rate were calculated. With SPECT, polar maps of the LV myocardium were divided into 20 segments. The regional uptake and washout rate were calculated from semiquantitative 20-segment bull's-eye analysis. RESULTS: The early uptake was significantly lower in group C than in the control group (P < 0.01). The washout rate was progressively higher in group A, group B, and group C (P < 0.01). Reduced regional early uptake was found in 2.9 +/- 3.4 (group A), 4.1 +/- 4.7 (group B), and 7.4 +/- 4.3 (group C) segments, respectively. In group C, regional early uptake was significantly reduced, predominantly in the interventricular septal wall, and regional washout rate was increased in the apex and lateral wall. CONCLUSION: These results suggest that cardiac sympathetic nerve abnormalities in patients with HCM may advance with development of LV systolic dysfunction and dilatation and that (123)I-MIBG myocardial scintigraphy may be a useful tool for the evaluation of pathophysiologic changes in HCM.     

Improvement of cardiac sympathetic innervation by renal transplantation.

Chronic renal failure (CRF) patients on dialysis frequently show reduced heart rate variability (HRV), which has been reported to be corrected by renal transplantation. Recently, (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy has been used to evaluate cardiac sympathetic innervation, and uremic patients often show marked abnormalities of cardiac (123)I-MIBG uptake. We investigated whether renal transplantation can improve cardiac (123)I-MIBG uptake in patients with CRF on dialysis. METHODS: We analyzed time- and frequency-domain measures of 24-h HRV and cardiac (123)I-MIBG scintigraphy before and 1-3 mo after renal transplantation in 13 CRF patients on dialysis and in 10 control subjects. RESULTS: Both 24-h HRV and cardiac (123)I-MIBG uptake were significantly abnormal in the patients before transplantation compared with the control subjects. After transplantation, (123)I-MIBG washout rate from the myocardium significantly decreased from 46% +/- 21% to 20% +/- 22% (P = 0.006), and the heart-to-mediastinum ratio of (123)I-MIBG uptake in the late image significantly increased from 1.74 +/- 0.39 to 2.06 +/- 0.39 (P = 0.006). On the other hand, HRV measures tended to increase after transplantation but the changes did not reach statistical significance (P > 0.05). CONCLUSION: Renal transplantation provides the improvement of uremic cardiac sympathetic neuropathy assessed by (123)I-MIBG imaging, which may be a more sensitive or at least an earlier marker than HRV.     

Ongoing myocardial damage relates to cardiac sympathetic nervous disintegrity in patients with heart failure

Iodine-123-metaiodobenzylguanidine (123I-MIBG) has been used to assess the integrity and function of the cardiac sympathetic nervous system in patients with heart failure. Heart-type fatty acid binding protein (H-FABP) is released into the circulation when the myocardium is injured, and H-FABP has been recently used as a novel marker for the diagnosis of ongoing myocardial damage. OBJECTIVE: The aim of the present study was to compare cardiac sympathetic nervous activity assessed by 123I-MIBG imaging with serum levels of H-FABP in patients with heart failure. METHODS: Fifty patients with chronic heart failure were studied. 123I-MIBG imaging was carried out at 30 min (early) and 240 min (delayed) after the tracer injection. We measured serum levels of H-FABP using a sandwich enzyme linked immunosorbent assay. RESULTS: Heart to mediastinum (H/M) ratios of 123I-MIBG decreased and washout rate increased with higher New York Heart Association (NYHA) functional class. H-FABP, norepinephrine and brain natriuretic peptide (BNP) levels increased as the severity of NYHA class advanced. Delayed H/M ratio was significantly correlated with H-FABP (r = -0.296, p = 0.029) and BNP (r = -0.335, p = 0.0213). Myocardial washout rate of 123I-MIBG was also correlated with H-FABP (r = 0.469, p < 0.001), norepinephrine (r = 0.433, p = 0.005), and BNP (r = 0.465, p = 0.001). CONCLUSIONS: These data suggest that cardiac sympathetic nervous activation was associated with ongoing cardiomyocyte damage characterized by an elevated serum level of H-FABP in patients with heart failure. 123I-MIBG imaging is an appropriate approach to evaluate non-invasively not only cardiac sympathetic nervous activity, but also latent ongoing myocardial damage in the failing heart.     

Evaluation of probable or possible dementia with lewy bodies using 123I-IMP brain perfusion SPECT, 123I-MIBG, and 99mTc-MIBI myocardial SPECT.

We evaluated the diagnostic usefulness of combination studies with a statistical mapping method in N-isopropyl-p-(123)I-iodoamphetamine ((123)I-IMP) brain perfusion SPECT, cardiac sympathetic nerve function by (123)I-metaiodobenzylguanidine ((123)I-MIBG), and myocardial function by electrocardiographically gated (99m)Tc-sestamibi ((99m)Tc-MIBI) SPECT for patients with probable or possible dementia with Lewy bodies (DLB). METHODS: Twelve patients with probable DLB (7 male, 5 female; mean age +/- SD, 72.3 +/- 5.63 y; range, 65-82 y) and 9 patients with possible DLB (3 male, 6 female; mean age +/- SD, 73.1 +/- 9.23 y; range, 59-88 y) were enrolled in this study. (123)I-IMP SPECT images were analyzed with 3-dimensional stereotactic surface projections (3D-SSP) and the severity of ischemia was classified objectively using quantitatively analytic and display software; stereotactic extraction estimation (SEE) methods were compared with a normal database. In addition, we evaluated (123)I-MIBG heart-to-mediastinum (H/M) uptake ratios. Moreover, we performed (99m)Tc-MIBI SPECT to evaluate myocardial perfusion and the left ventricular ejection fraction (LVEF) compared with a normal database. RESULTS: 3D-SSP images of group comparison with healthy control subjects showed significantly decreased perfusion in the parietotemporal, occipital cortex, posterior cingulated, and precuneus regions in the probable DLB group but no significant reduction in the possible DLB group. Mean H/M ratios in the probable DLB group were significantly lower than those of the possible DLB group and the control group, respectively. Ten of 12 patients (83.3%) with probable DLB and 1 of 9 patients (11.1%) with possible DLB showed severe reduction in the bilateral occipital lobe and also a low (123)I-MIBG uptake. One patient (8.3%) with probable DLB and 2 patients (22.2%) with possible DLB showed no bilateral occipital hypoperfusion but showed low (123)I-MIBG uptake. One patient (8.3%) with probable DLB and 6 patients (66.7%) with possible DLB showed no occipital hypoperfusion and normal (123)I-MIBG uptake. (99m)Tc-MIBI gated SPECT did not indicate any wall motion abnormality in any subjects. CONCLUSION: These results suggest that combined examination of cerebral blood flow with 3D-SSP and SEE analysis, and cardiac sympathetic nerve function with (123)I-MIBG, would be a useful supporting diagnostic method in patients with DLB-particularly, in possible DLB and when cerebral blood flow does not indicate occipital hypoperfusion.     

Dynamic123I-MIBG SPECT reflects sympathetic nervous integrity and predicts clinical outcome in patients with chronic heart failure

123I-metaiodobenzylguanidine (123I-MIBG) is useful for assessment of the severity and prognosis of patients with chronic heart failure (CHF). To examine 123I-MIBG kinetics in the early phase soon after tracer injection, we performed dynamic single photon emission computed tomography (SPECT) in 76 patients with CHF and 17 control subjects. The consecutive 15 images of 2 min-dynamic SPECT were acquired for 30 min after injection. From 0 to 4 min, a significant amount of radioactivity existed in the blood pool, thus we calculated washout rate of 123I-MIBG from 4 to 30 min (%WR-E). Patients were followed up with an end-point of cardiac death or re-hospitalization for 16 months (6-30 months). As the NYHA functional class advanced, %WR-E increased (control, NYHA class I, II, and III: 9 +/- 4%, 10 +/- 5%, 12 +/- 5%, and 17 +/- 5%*, respectively, *p < 0.01 vs. all other groups). Significant correlation was found between %WR-E and conventional WR from 30 min to 240 min (r = 0.606, p < 0.0001). %WR-E was positively correlated with left ventricular end-diastolic dimension (r = 0.372, p < 0.01) and was inversely correlated with left ventricular fractional shortening (r = -0.316, p < 0.02). The normal upper limit of %WR-E was defined as mean + 2SD value of 17 control subjects (17.1%). Patients with abnormally rapid %WR-E levels had a higher cardiac event rate than those with normal %WR-E levels (57% vs. 12%, p < 0.0001). These data suggest that washout rate of 123I-MIBG in the early phase from 4 min to 30 min (%WR-E) reflects cardiac sympathetic nervous integrity and is useful to evaluate the severity and prognosis of patients with CHF. The present results indicate a potential role of dynamic SPECT in shortening the 123I-MIBG imaging protocol.     

Evaluation of the cardiac autonomic nervous system in spontaneously non-insulin-dependent diabetic rats by123I-metaiodobenzylguanidine imaging

OBJECTIVE: To evaluate the sensitivity of 123I-labeled metaiodobenzylguanidine (123I-MIBG) scintigraphy in detecting diabetic autonomic nervous system disorders. MATERIALS AND METHODS: Thirty-one-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of spontaneous non-insulin-dependent diabetes mellitus, were maintained for 8 weeks with or without 30% sucrose solution as a drinking water (n = 3 each). Long-Evans Tokushima Otsuka (LETO) rats (n = 3), served as controls. Plasma glucose and insulin levels were measured, and 123I-MIBG scintigraphy was performed with a gamma camera equipped with a pinhole collimator for animals. Plasma and cardiac tissue cathecolamine levels were also determined. RESULTS: Plasma glucose levels of OLETF rats with and without sucrose loading (554+/-106 and 141+/-1.5 mg/dl respectively) were significantly higher than those of LETO rats (116+/-3.7 mg/dl). Norepinephrine concentrations in heart and plasma tended to be lower in diabetic rats. The washout rate of 123I-MIBG in diabetic rats was significantly higher than the rate in control rats. Cardiac uptake of 123I-MIBG, calculated as % dose/g of tissue, was significantly lower in diabetic rats than in control rats. CONCLUSION: These results suggest that myocardial 123I-MIBG scintigraphy is suitable for assessing cardiac sympathetic activity noninvasively in diabetic states, even in the early stages.     

Decreased myocardial beta-adrenergic receptor density in relation to increased sympathetic tone in patients with nonischemic cardiomyopathy.

Cardiac sympathetic function plays an important role in the regulation of left ventricular (LV) function and the pathophysiology of LV dysfunction. (11)C-CGP-12177 ((11)C-CGP) has been used to assess myocardial beta-adrenergic receptor (beta-AR) density in vivo using PET. The aim of this study is to measure myocardial beta-AR density in patients with nonischemic cardiomyopathy and to compare the measurements with various standard parameters of heart failure (HF), particularly with presynaptic function assessed by (123)I- metaiodobenzylguanidine ((123)I-MIBG) imaging. METHODS: (11)C-CGP PET was performed on 16 patients with nonischemic cardiomyopathy and 8 age-matched healthy volunteers using a double injection method. A (11)C-CGP dynamic scan for 75 min was performed after the injection of (11)C-CGP with a high specific activity. After 30 min, (11)C-CGP with a low specific activity was injected. The beta-AR density of the whole LV was calculated on the basis of the graphical analysis method. Additionally, beta-AR density was compared with LV ejection fraction (LVEF), sympathetic presynaptic function assessed using (123)I-MIBG kinetics, and neurohormonal parameters. RESULTS: The beta-AR density of patients was significantly lower than that of healthy volunteers (3.80 +/- 0.96 vs. 7.70 +/- 1.92 pmol/mL; P < 0.0001). In the patients, beta-AR density correlated significantly with LVEF (r = 0.62, P < 0.05). Furthermore, beta-AR density correlated significantly with the (123)I-MIBG washout rate (r = -0.68, P < 0.01) and delayed heart-to-mediastinum ratio (H/M ratio) (r = 0.61, P < 0.05). On the other hand, the correlation between beta-AR density and early H/M ratio was not significant (r = 0.40, P = 0.13). The beta-AR density of patients with severe HF (New York Heart Association functional [NYHA] class III) was significantly lower than that of those with NYHA functional class I or class II HF (3.24 +/- 0.96 vs. 4.24 +/- 0.73 pmol/mL; P < 0.05). CONCLUSION: A reduction in beta-AR density measured by (11)C-CGP PET was observed in patients with nonischemic cardiomyopathy. This downregulation may be due to the increased presynaptic sympathetic tone as assessed by (123)I-MIBG imaging.     

Role of interleukin-6 levels in cardiovascular autonomic dysfunction in type 2 diabetic patients

PURPOSE: Increased serum interleukin-6 (IL-6) levels are associated with an increased risk of cardiovascular disease, and cardiovascular autonomic dysfunction is associated with high mortality in type 2 diabetic patients. However, the relationship between IL-6 levels and cardiovascular autonomic dysfunction has not been fully elucidated. The aim of this study was to determine whether serum IL-6 levels are associated with cardiovascular autonomic dysfunction in type 2 diabetic patients. METHODS: Eighty type 2 diabetic patients who did not have organic heart disease were categorized into a high IL-6 group (>2.5 pg/ml, n = 40, age 59 +/- 12 years) or a non-high IL-6 group (<2.5 pg/ml, n = 40, 61 +/- 12 years). Cardiac autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations and (123)I-metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: The body mass index values (BMI), fasting insulin levels and homeostasis model assessment index values were higher in the high IL-6 group than in the non-high IL-6 group (p < 0.01). Early and delayed (123)I-MIBG myocardial uptake values were lower (p < 0.01), and the percent washout rate of (123)I-MIBG was higher (p < 0.05) in the high IL-6 group than in the non-high IL-6 group. Furthermore, multiple regression analysis revealed that the IL-6 level was independently predicted by the BMI and the myocardial uptake of (123)I-MIBG during the delayed phase. CONCLUSIONS: The results indicate that elevated IL-6 levels are associated with depressed cardiovascular autonomic function and obesity in type 2 diabetic patients.     

Sympathetic denervation and reinnervation after the maze procedure.

We evaluated serial changes in cardiac sympathetic nerve distribution using 123I-metaiodobenzylguanidine (123I-MIBG) after the Maze procedure. The Maze procedure, in which multiple incisions are made in the atrium, has been concomitantly performed with mitral valve (MV) surgery in an attempt to eliminate atrial fibrillation (AF). Although attenuation of the sinoatrial node response to exercise and a reduction of left ventricular function (left ventricular ejection fraction [LVEF]) in early stages after the Maze procedure have been suggested, factors leading to these changes have not been clarified. METHODS: Thirteen patients with MV disease were enrolled in this study. Six of them had undergone MV surgery and the Maze procedure (Maze+), and 7 had undergone MV surgery without the Maze procedure (Maze-). All patients underwent cardiac 123I-MIBG imaging preoperatively and 10 d and 1 y after surgery to assess 123I-MIBG uptake (heart-to-mediastinum count ratio of early planar images [H/M]) and the washout rate (WR). Radionuclide ventriculography was also performed to calculate LVEF 3 d after each 123I-MIBG imaging. RESULTS: The LVEF of the Maze+ group significantly decreased 10 d after surgery (44.2 +/- 4.8; mean +/- SD) compared with that before surgery (60.3 +/- 6.9; P < 0.05) and significantly increased at 1 y (65.2 +/- 2.9) compared with that at 10 d (P < 0.05). In the Maze- group, there was no significant change 10 d (53.0 +/- 12.3) and 1 y (58.6 +/- 4.8) after surgery compared with that before surgery (60.4 +/- 4.6) (P = not significant, each). In the Maze+ group, the H/M (1.51 +/- 0.18) was significantly lower at 10 d after than that at the preoperative stage (1.90 +/- 0.25; P < 0.05) but significantly recovered at 1 y (2.23 +/- 0.18; P < 0.05) with a similar transient increase in the WR (36.7% +/- 6.1% at preoperative stage; 46.9% +/- 3.4% at 10 d; 39.9% +/- 6.5% at 1 y; P < 0.05, each). On the other hand, the Maze- group did not show a significant change in the H/M (1.94 +/- 0.32, 2.06 +/- 0.18, and 2.13 +/- 0.17, respectively; P = not significant, each) but did exhibit a significant decrease in the WR (40.4% +/- 5.1%, 37.0% +/- 5.1%, and 32.9% +/- 2.5%, respectively; P < 0.05, each). Changes in the H/M of both groups significantly correlated with the change in LVEF (r = 0.82; P < 0.05), and the WR showed a significant inverse correlation with changes in the LVEF (r = -0.81; P < 0.05). CONCLUSION: Cardiac sympathetic nerves were denervated at early stage and reinnervated at late stage after the Maze procedure. Such adrenergic nerve changes may be correlated, at least in part, with changes in left ventricular function after this procedure.     

Myocardial 123I-MIBG kinetics in acutely hypothyroid patients with differentiated thyroid carcinoma.

Marked changes in cardiac function have been noted in patients with hyperthyroidism or hypothyroidism due both to changes in sympathetic system function and to biochemical modifications of myocardial tissue. Metaiodobenzylguanidine (MIBG), an analogue of norepinephrine, can be used to evaluate myocardial sympathetic tone. Here, we report myocardial 123I-MIBG kinetics in patients with differentiated thyroid carcinoma undergoing acute hypothyroidism followed by hormonal replacement as part of their routine clinical follow-up. Ten patients with differentiated thyroid carcinoma in acute hypothyroidism (A) and on hormonal replacement with thyroxine (150 micrograms.day-1) and triiodothyronine (20 micrograms.day-1) (B) underwent scintigraphic imaging 20 min and 4 h after injection of 111 MBq of ultra-high specific activity 123I-MIBG. No patient had cardiac disease or was taking medications that could interfere with cardiac or autonomic system function. Cardiac MIBG kinetics (heart-to-mediastinum, H/M, ratio and myocardial washout rate), serum norepinephrine, T3, T4, FT3, FT4, TSH, CPK, CPK-MB, blood pressure and ECG were evaluated. Systolic and diastolic blood pressure did not differ significantly between state A and state B. In the acute hypothyroid state (A), the prevalence of non-specific ST-T abnormalities was 70% and heart rate was significantly different (P < 0.001) than in state B. Norepinephrine and CPK-MB levels were higher during hypothyroidism, but this did not reach statistical significance. A positive correlation between early H/M and delayed H/M in the hypothyroid state (r = 0.57) and an even higher positive correlation between early H/M and delayed H/M in the euthyroid state (r = 0.91) were seen. The myocardial and mediastinal MIBG washout rates were significantly different between the hypothyroid and euthyroid states (P < 0.05), whereas the lung washout rate did not differ significantly between the two metabolic states. We conclude that the myocardial washout rate during hypothyroidism is clearly increased (P < 0.005) with a subclinical derangement of myocardial adrenergic innervation, which is rapidly reversed with hormonal therapy.     

Cardiac 123I-MIBG reflects left ventricular functional reserve in patients with nonobstructive hypertrophic cardiomyopathy.

Little is known about the relation between left ventricular (LV) functional reserve in response to exercise and cardiac sympathetic nervous function in patients with nonobstructive hypertrophic cardiomyopathy (HCM). We investigated whether an assessment of cardiac sympathetic nervous function by myocardial (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy might provide a sign of an abnormal LV functional reserve in response to exercise-induced beta-adrenergic stimulation in patients with HCM. METHODS: Thirty HCM patients underwent (123)I-MIBG scintigraphy and echocardiography at rest and subsequent biventricular cardiac catheterization at rest and during dynamic exercise. LV pressures were measured using a micromanometer-tipped catheter system. The early and delayed (123)I-MIBG images were quantified as a heart-to-mediastinum ratio (H/M). The plasma levels of brain natriuretic peptide (BNP) and norepinephrine (NE) were also measured. RESULTS: Patients were divided into 2 groups according to the delayed (123)I-MIBG H/M: group I consisted of 12 patients with a delayed H/M of < or =1.8 and group II had 18 patients with a delayed H/M of >1.8. Both the percentage increase from rest to exercise in LV isovolumic contraction (LV dP/dt(max)) and the percentage shortening of LV pressure half-time (T(1/2)) as an index of isovolumic relaxation were significantly less in group I than in group II (P < 0.05, respectively). A significant linear correlation was observed between the percentage increase in LV dP/dt(max) and (123)I-MIBG H/Ms (early H/M: r = 0.49, P < 0.01; delayed H/M: r = 0.54, P < 0.005, respectively). A significant linear correlation was also observed between the percentage shortening in T(1/2) and (123)I-MIBG H/Ms (early H/M: r = 0.58, P < 0.001; delayed H/M: r = 0.64, P < 0.0005, respectively). The plasma NE levels were significantly higher in group I than in group II (P < 0.01), whereas the plasma BNP levels were comparable in the 2 HCM groups. CONCLUSION: beta-Adrenergic enhancement of LV function during exercise may depend on the extent of cardiac sympathetic nervous innervation in HCM patients. Resting myocardial (123)I-MIBG scintigraphy can noninvasively evaluate LV functional reserve in response to exercise in patients with nonobstructive HCM.     

Correlation between cardiac norepinephrine overflow during exercise and cardiac 123I-MIBG uptake in patients with chronic heart failure.

Cardiac (123)I-metaiodobenzylguanidine ((123)I-MIBG) uptake is reduced in chronic heart failure, and its reduction is reported to relate to the decrease in exercise capacity. Reduced (123)I-MIBG uptake may predict an inadequately reduced adrenergic drive to the heart during cardiac sympathetic stimulation, including exercise. However, there is little information about the relationship between cardiac (123)I-MIBG uptake at rest and norepinephrine (NE) release during exercise in relation to the exercise capacity in the failing heart. The aim of this study was to examine whether cardiac (123)I-MIBG uptake at rest can predict cardiac sympathetic activity during exercise in patients with chronic heart failure. We determined how cardiac (123)I-MIBG uptake at rest relates to NE overflow from the heart during symptom-limited graded exercise in such patients. METHODS: Twelve patients (mean +/- SD, 52 +/- 12 y) with chronic stable heart failure performed symptom-limited graded exercise tests under catheterizations with a 4-min stage using a supine bicycle ergometer within 2 wk after (123)I-MIBG imaging. NE concentrations in the arterial and coronary sinus blood (NE(A) and NE(CS), respectively) were measured at each exercise stage, and NE overflow was approximated by the difference between NE(CS) and NE(A) (NE(CS-A)). RESULTS: The left ventricular ejection fraction at rest was 47% +/- 16% and peak oxygen uptake was 17.7 +/- 5.1 mL/kg/min. The heart-to-mediastinum uptake ratio of the delayed (123)I-MIBG image (1.00 - 1.72; mean +/- SD, 1.30 +/- 0.19) correlated with NE(CS-A) at peak exercise (r = 0.80, P < 0.01) and peak heart rate (r = 0.73, P < 0.01) but not with peak oxygen uptake. CONCLUSION: Cardiac (123)I-MIBG uptake of the delayed image can predict the degree of the increase in adrenergic drive to the heart during sympathetic stimuli induced by exercise in patients with chronic heart failure.     

Kinetics of 123I-MIBG after acute myocardial infarction and reperfusion therapy.

Metaiodobenzylguanidine (MIBG) washout from the myocardium has been thought to reflect sympathetic nerve tone. After acute myocardial infarction, however, little is known about this parameter. The aim of this study was to determine the significance of cardiac washout after myocardial infarction and early reperfusion by investigating MIBG kinetics and correlating those kinetics to clinical parameters. METHODS: Sixty patients with acute myocardial infarction underwent planar MIBG and thallium imaging within 14 d of early reperfusion therapy. Global uptake and washout in myocardium, lungs and liver were calculated from early and delayed images. A regional analysis of myocardial kinetics in normal and infarcted myocardium and in an infarct border zone was also performed. Scintigraphic data were correlated with heart-rate variability as an electrophysiologic marker for autonomic tone and prevalence of arrhythmia in 52 patients. Heart-rate variability was described by time-domain indices from long-term electrocardiogram recordings. An age-matched normal control group for MIBG consisted of 10 individuals without heart disease. RESULTS: The infarct patients had preserved left-ventricular ejection fraction (LVEF) (56% +/- 17%). Although late myocardial uptake was expectedly lower in infarct patients compared with healthy volunteers (2.36 +/- 0.66 versus 2.80 +/- 0.55; P = 0.04), global myocardial MIBG washout was faster (11.6% +/- 7.9% versus 0.2% +/- 10.2%, respectively; P = 0.002). Lung and liver kinetics did not differ in patients and healthy volunteers. Global MIBG washout showed a weak but significant positive correlation with the baseline heart rate (r = 0.28, P = 0.03) and an inverse correlation with LVEF (r = -0.28, P = 0.04). Washout was faster in a subgroup of 8 patients with reduced heart-rate variability (16.5% +/- 9.9% versus 10.3% +/- 8.3%; P = 0.04). Regional analysis revealed similar degrees of enhanced MIBG washout for infarcted (low perfusion, low MIBG uptake) and remote myocardium (normal perfusion, high MIBG uptake), whereas the border zone (normal perfusion, low MIBG uptake) showed a nonsignificant trend toward higher washout. CONCLUSION: After myocardial infarction, changes in MIBG kinetics occur specifically in the myocardium, whereas kinetics in lung and liver remain unchanged. Even in patients with left-ventricular function preserved by reperfusion therapy, MIBG washout is abnormal and globally increased. Enhanced washout may reflect increased sympathetic nerve tone and represent increased catecholamine turnover or impaired reuptake in the subacute phase of myocardial infarction.     

Improved labelling of no-carrier-added 123I-MIBG and preliminary clinical evaluation in patients with ventricular arrhythmias.

Meta-[123I]iodobenzylguanidine (123I-MIBG) is currently used to assess myocardial sympathetic innervation by single photon emission tomography (SPET). In recent studies, an enhanced cardiac uptake of 123I-MIBG with high specific activity has been reported, suggesting the clinical potential of no-carrier-added (n.c.a.) 123I-MIBG in the assessment of abnormalities in cardiac sympathetic function. This paper describes the preparation of n.c.a. 123I-MIBG by non-isotopic Cu(I)-assisted [123I]iododebromination and by [123I]iododestannylation, both resulting in n.c.a. 123I-MIBG with radiochemical yields of 88 +/- 6% and high specific activity (> or = 6.3 TBq.mumol-1) in a total synthesis time of less than 50 min. The diagnostic potential of n.c.a. 123I-MIBG (> 6.3 TBq.mumol-1) was studied in 13 patients (nine patients with malignant ventricular arrhythmias and four patients suspected of phaeochromocytoma) and compared to commercial 123I-MIBG (approximately 75 MBq.mumol-1) using a dual-headed SPET camera (MULTISPECT II). High specific activity results in higher 123I-MIBG uptake in the heart and in the liver in all patients. The calculated heart-to-lung and heart-to-liver count ratios 4.5 h post-injection increased by 22 +/- 6% and 10 +/- 5% with n.c.a. 123I-MIBG compared to commercial 123I-MIBG respectively. In contrast, no significant correlation between the specific activity of 123I-MIBG and lung uptake could be established in this study. Analysis of radioactivity in blood after the intravenous injection of n.c.a. and commercially available 123I-MIBG showed an initial rapid clearance of radioactivity from blood, followed by a plateau from 60 min onwards. Within the first 24 h, more than 85% of the plasma activity was unchanged 123I-MIBG. The free 123I-iodide concentration determined 24 h post-injection was 2 +/- 1% with commercial 123I-MIBG and 3 +/- 2% with n.c.a. 123I-MIBG. In conclusion, the results of this investigation indicate that n.c.a. 123I-MIBG is a promising clinical tool for imaging myocardial sympathetic dysfunction by SPET. High specific activity n.c.a. 123I-MIBG can now be prepared by simple one-step methods giving high radiochemical yields and high purity suitable for clinical application. This encourages the further clinical validation of n.c.a. 123I-MIBG on a large scale.