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.     

Clinical implications of cardiac (123)I-meta-iodobenzylguanidine scintigraphy and cardiac natriuretic peptides in patients with heart disease

The purpose of this study was to evaluate whether or not cardiac sympathetic nerve activity, using (123)I-meta-iodobenzylguanidine ((123)I-MIBG) imaging, and cardiac natriuretic peptides (atrial and brain, ANP and BNP) were independent predictors of cardiac events, and, if so, which was the stronger predictor. Planar (123)I-MIBG images were obtained from 62 patients with heart disease. Plasma ANP and BNP levels, left ventricular ejection fraction (LVEF) by echocardiography, serum total cholesterol and triglyceride were measured. (123)I-MIBG was assessed as the heart-to-mediastinum (H/M) ratio of the delayed image and the washout rate (WoR) from the early to the delayed image. Patients were followed up for an average of 16.2 months, and 12 of 62 patients had cardiac events. Patients with events had significantly lower LVEF and H/M ratio compared with those without events. They had significantly higher WoR, ANP and BNP. By multivariate Cox proportional hazard analysis, (123)I-MIBG (H/M or WoR), ANP and BNP were independent predictors for cardiac events. Event-free survival using a Kaplan-Meier model, with a threshold value of 2.0 for H/M and 45% for WoR, showed that patients with H/M<2.0 and/or WoR>45% had a significantly poorer prognosis. These results suggest that (123)I-MIBG imaging and cardiac natriuretic peptides are useful tools for the evaluation of patients with heart disease, and that cardiac sympathetic nerve activity is a stronger predictor of cardiac events.     

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.     

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.     

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.     

Effects of carvedilol on myocardial sympathetic innervation in patients with chronic heart failure.

Carvedilol is a beta-blocking agent with antioxidant properties that has been shown to improve survival in chronic heart failure (CHF). Previous open-label studies have suggested that its use may have positive effects on the abnormalities of cardiac sympathetic innervation integrity and functioning. The present study aimed to test the hypothesis that carvedilol exerts its beneficial effects on hemodynamics in parallel with an action on myocardial sympathetic activity and with its antioxidant property. METHODS: A randomized, multicenter, double-blind, placebo-controlled study of carvedilol was conducted on 64 CHF patients. Patients underwent-before and after 6 mo of therapy with either carvedilol or placebo-measurements of cardiac sympathetic activity, circulating catecholamine level, and hemodynamic indices. Myocardial meta-(123)I-iodobenzylguanidine ((123)I-MIBG) uptake was used to assess the changes in myocardial sympathetic activity. The antioxidant properties of the plasma were assessed by measuring the percentage of nonhemolyzed erythrocytes and the volume of plasma capable of inhibiting 50% of hemolysis after an oxidative stress. Echographic left ventricular (LV) diameters, radionuclide LV ejection fraction (LVEF), and exercise cardiopulmonary capacity were measured to evaluate the hemodynamic response. RESULTS: End-diastolic and end-systolic LV diameters decreased (both P < 0.05) and LVEF increased (P = 0.03) in the carvedilol group, whereas these parameters remained unchanged in the placebo group. Carvedilol did not alter the submaximal exercise cardiopulmonary capacity or the circulating catecholamine level. The beneficial hemodynamic effects in the carvedilol group were associated with an increase in myocardial (123)I-MIBG uptake as assessed by both planar and tomographic imaging (P < 0.01). Carvedilol had no detectable effect on antioxidant properties of the plasma. CONCLUSION: The benefits of carvedilol on resting hemodynamics appear to be associated with a partial recovery of cardiac adrenergic innervation functioning without detectable antioxidant effect in the plasma.     

Scintigraphic differentiation between two forms of primary dysautonomia early after onset of autonomic dysfunction: value of cardiac and pulmonary iodine-123 MIBG uptake

Primary dysfunction of the autonomic nervous system can be observed in patients with Parkinson's disease and those with multiple system atrophy. However, the fate of the two diseases differs considerably and leads to different strategies for patient management. Differentiation of the two diseases currently requires a combination of several clinical and electrophysiological tests. First studies of myocardial innervation using iodine-123 metaiodobenzylguanidine (MIBG) indicated a possible role of scintigraphy for this purpose. An increase in the pulmonary uptake of 123I-MIBG has been reported in secondary dysautonomias. Whether sympathetic innervation of the lung is affected in primary dysautonomias is currently unknown. Therefore, cardiac and pulmonary uptake of 123I-MIBG was studied in 21 patients with Parkinson's disease, 7 patients with multiple system atrophy and 13 age- and sex-matched controls. Thoracic images were obtained in the anterior view 4 h after intravenous injection of 185 MBq 123I-MIBG, at which time the maximum neuronal uptake is reached. All patients with Parkinson's disease had significantly lower cardiac uptake of 123I-MIBG than patients with multiple system atrophy and controls. Sympathetic innervation of the lung was not affected in either disease. It is concluded that scintigraphy with 123I-MIBG appears to be a useful tool for differentiation between Parkinson's disease and multiple system atrophy early after onset of autonomic dysfunction.     

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.     

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.     

Improvement of cardiac neuronal function after carvedilol treatment in dilated cardiomyopathy: a 123I-MIBG scintigraphic study.

Carvedilol can induce important clinical and hemodynamic improvements in patients with chronic heart failure resulting from severe left ventricular (LV) dysfunction. This study examines the impact of carvedilol on cardiac neuronal function using 123I-metaiodobenzylguanidine (MIBG) scintigraphy in dilated cardiomyopathy. METHODS: Twenty-two patients with chronic heart failure (19 men, 3 women; mean age, 54 y; age range, 34-64 y) assessed as New York Hospital Association (NYHA) class II or III and with initial resting radionuclide LV ejection fractions (LVEF) < 0.40 were enrolled in the study. Patients had long histories of symptomatic LV dysfunction despite optimal diuretics and angiotensin-converting enzyme inhibitor treatment. Over a 6-mo period, 50 mg/day carvedilol was administered to these patients. Planar 123I-MIBG scintigraphy provided measurements of cardiac neuronal uptake (as heart-to-mediastinum count activity ratio [HMR]), 4h after intravenous injection of 185 MBq MIBG. Hemodynamic, clinical, radionuclide LVEF and HMR data measured at the outset and after 6 mo of carvedilol were compared. RESULTS: Resting heart rate decreased from 81 +/- 13 to 71 +/- 9 bpm (P = 0.003). After carvedilol therapy NYHA functional classification for these patients improved from 2.6 +/- 0.5 to 2.3 +/-0.5 (P = 0.04), LVEF improved from 22% +/- 9% to 30% +/- 13% (P = 0.005), and HMR improved from 145% +/- 23% to 170% +/- 25% (P = 0.0001). CONCLUSION: Carvedilol induces improvements of clinical symptoms and cardiac neuronal and systolic functions in patients with dilated cardiomyopathy and chronic optimal treatment.     

Scintigraphic differentiation between two forms of primary dysautonomia early after onset of autonomic dysfunction: value of cardiac and pulmonary iodine-123 MIBG uptake

Primary dysfunction of the autonomic nervous system can be observed in patients with Parkinson’s disease and those with multiple system atrophy. However, the fate of the two diseases differs considerably and leads to different strategies for patient management. Differentiation of the two diseases currently requires a combination of several clinical and electrophysiological tests. First studies of myocardial innervation using iodine-123 metaiodobenzylguanidine (MIBG) indicated a possible role of scintigraphy for this purpose. An increase in the pulmonary uptake of ¹²³I-MIBG has been reported in secondary dysautonomias. Whether sympathetic innervation of the lung is affected in primary dysautonomias is currently unknown. Therefore, cardiac and pulmonary uptake of ¹²³I-MIBG was studied in 21 patients with Parkinson’s disease, 7 patients with multiple system atrophy and 13 age- and sex-matched controls. Thoracic images were obtained in the anterior view 4 h after intravenous injection of 185 MBq ¹²³I-MIBG, at which time the maximum neuronal uptake is reached. All patients with Parkinson’s disease had significantly lower cardiac uptake of ¹²³I-MIBG than patients with multiple system atrophy and controls. Sympathetic innervation of the lung was not affected in either disease. It is concluded that scintigraphy with ¹²³I-MIBG appears to be a useful tool for differentiation between Parkinson’s disease and multiple system atrophy early after onset of autonomic dysfunction. Received 2 December 1999 and in revised form 17 February 2000     

Cardiac sympathetic denervation from the early stage of Parkinson's disease: clinical and experimental studies with radiolabeled MIBG.

Autonomic disorder is not infrequent in patients with akinetic-rigid syndromes, including idiopathic Parkinson's disease. In the advanced stage of Parkinson's disease, abnormal blood pressure responses, such as orthostatic hypotension and abnormal circadian blood pressure rhythm, may occur. Few cases of reduced 123I-metaiodobenzylguanidine (MIBG) accumulation in the heart or limbs of Parkinson's disease patients have been reported. However, whether reduced accumulation is caused by damage to the postganglionic sympathetic nervous system or by central autonomic failure corresponding to abnormalities in blood pressure regulation is unknown. METHODS: We evaluated sympathetic denervation in 32 Parkinson's disease patients using 123I-MIBG cardiac scintigraphy and compared the findings with those for autonomic dysfunction detected by orthostatic hypotension and diurnal blood pressure variation. Cardiac 125I-MIBG accumulation was also determined in an experimental model of Parkinson's disease using mice pretreated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). RESULTS: Cardiac 123I-MIBG accumulation 15 min after injection and 4 h after injection was markedly reduced in the Parkinson's disease patients (heart-to-mediastinum ratio: 1.58 +/- 0.37 and 1.33 +/- 0.28, respectively) compared with 7 healthy volunteers (2.42 +/- 0.27 and 2.60 +/- 0.15, respectively). This reduction was observed even at the earlier stages of physical activity or disease duration and also in patients with normal blood pressure response and variation, indicating that the marked decrease in cardiac 123I-MIBG accumulation may be a special feature of Parkinson's disease. Pretreatment with a total dose of 100 mg/kg MPTP, which is the standard dose used to destroy the dopaminergic neurons in models of Parkinson's disease, significantly reduced cardiac 125I-MIBG accumulation in C57BL/6 mice. Interestingly, the reduction of 125I-MIBG accumulation was still significant when MPTP was reduced to 5 mg/kg. These findings indicated that the postganglionic sympathetic nerves may be damaged by MPTP or unknown toxic substrates in experimental or human Parkinson's disease during the early stage, because dopaminergic neurons and sympathetic nerves are substantially similar in their plasma membrane transporters. CONCLUSION: Cardiac scintigraphy with 123I-MIBG may be used as a new imaging approach in the diagnosis and characterization of akinetic-rigid syndromes, especially Parkinson's disease.     

Cardiac applications of 123I-mIBG imaging

Cardiac autonomic innervation plays a key role in maintaining hemodynamic and electrophysiologic harmony. Cardiac sympathetic function is adversely altered in many disease states, such as congestive heart failure, myocardial ischemia, and diabetes. (123)I-mIBG, a sympathetic neurotransmitter radionuclide analog, aids in the detection of sympathetic innervation abnormalities and can be imaged with planar and single-photon emission computed tomographic techniques. Cardiac (123)I-mIBG uptake can be assessed by the heart mediastinal ratio (H/M), tracer washout rate, and focal uptake defects. These parameters have been widely studied and shown to correlate strongly and independently with congestive heart failure progression, cardiac arrhythmias, cardiac death, and all-cause mortality. There is accumulating evidence that (123)I-mIBG imaging can help to monitor a patient's clinical course and response to therapy. The ability to predict potentially lethal ventricular arrhythmias promises to help more accurately select patients for implantable cardioverter defibrillators, limiting unnecessary devices and identifying additional patients at risk who do not meet current guidelines. (123)I-mIBG shows potential to help determine whether greater risk and usually more expensive ventricular assist device therapies or cardiac transplantation might be needed. Although more investigation in larger populations is needed to strengthen previous findings, cardiac (123)I-mIBG imaging shows promise as a new technique for recognizing and following potentially life-threatening cardiac conditions.     

Cardiac death prediction and impaired cardiac sympathetic innervation assessed by MIBG in patients with failing and nonfailing hearts

Background  Although cardiac sympathetic nerve dysfunction is related to poor clinical outcome, a critical sympathetic dysfunction level for predicting cardiac death is still unclear. The current study was designed to investigate which indices derived from metaiodobenzylguanidine (MIBG) imaging have prognostic value compared with clinical and cardiac function variables, and to determine the threshold of cardiac MIBG activity for identifying patients likely to suffer cardiac death in both failing and nonfailing hearts. Methods and Results  Myocardial I-123-MIBG activity was quantified as a heart-to-mediastinum ratio in 414 consecutive patients, 173 (42%) of whom had symptomatic heart failure. After cardiac function measurements, patients were followed up with an end-point of cardiac or noncardiac death. During a mean follow-up period of 22 months, 37 cardiac deaths occurred: 23 resulted from heart failure, 9 were sudden cardiac deaths, and 5 were fatal myocardial infarctions. Multivariate analysis using the Wald χ² and the Cox proportional hazard model revealed that late heart-to-mediastinum ratio, the use of nitrates, early heart-to-mediastinum ratio, and left ventricular ejection fraction were independent predictors of cardiac death; late heart-to-mediastinum ratio, New York Heart Association (NYHA) class, the presence of previousmyocardial infarction, and age were independent predictors of heart failure and sudden cardiac death. Late heart-to-mediastinum ratio was the most powerful predictor of overall cardiac death among the variables. The Kaplan-Meier analysis showed that a late heart-to-mediastinum ratio of 1.74 or less, age greater than 60 years, the presence of myocardial infarction, and NYHA functional class 3 or 4 strongly indicated poor clinical outcomes. Furthermore, the more powerful incremental prognostic values were obtained by using MIBG imaging in combination with conventional clinical variables. Conclusions  Impaired cardiac sympathetic innervation assessed by MIBG activity has the greatest potential for predicting cardiac death and may be useful for identifying a threshold level for selecting patients at risk for death by heart failure, sudden cardiac death, and fatal myocardial infarction.     

Risk stratification in heart failure using ¹²³I-MIBG

Heart failure is a progressive, heterogeneous form of cardiovascular disease that requires treatment to be individualized depending on the presenting symptoms. A decision to use an implantable cardioverter-defibrillator (ICD) is based on chronic heart failure patients presenting with a New York Heart Association classification of II or III and a left ventricular ejection fraction (LVEF) less than or equal to 30%-35%. A large percentage of ICD devices, however, never deliver therapy during their lifetime, and as many as 33% of patients ineligible for an ICD (LVEF > 35%) die of sudden cardiac death. (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy identifies sympathetic nervous system dysfunction and has been shown to lead to better patient stratification. This article reviews the role of planar (123)I-MIBG global quantitation in improving differentiation of heart failure, regardless of the LVEF, to better identify those in whom an ICD is more likely to reap benefits. It goes on to explore the potential incremental benefit of SPECT-based regional quantitation to risk stratification and provides a case example in which (123)I-MIBG SPECT was used to inform a decision to not use an ICD in a patient eligible under the standard criteria.     

Iodine-123-metaiodobenzylguanidine imaging can predict future cardiac events in heart failure patients with preserved ejection fraction

Objective

Iodine-123-metaiodobenzylguanidine (¹²³I-MIBG) has been used to assess the function of the cardiac sympathetic nervous system in patients with chronic heart failure (HF). The usefulness of ¹²³I-MIBG imaging for evaluating patients with heart failure with preserved ejection fraction (HFPEF) has not been established.

Methods

We performed ¹²³I-MIBG scintigraphy and echocardiography and measured the plasma brain natriuretic peptide (BNP) levels of 117 consecutive HF patients (64 men, mean age 66 ± 14 years) with a left ventricular ejection fraction (LVEF) of ≥50% who were admitted to our hospital. Patients were divided into 2 groups according to the New York Heart Association (NYHA) functional class.

Results

The ¹²³I-MIBG delayed heart-to-mediastinum (H/M) ratio was significantly lower, and the washout rate (WR) was higher in patients with HFPEF with advanced NYHA functional class (NYHA functional class I and II vs. III: 1.90 ± 0.34 vs. 1.49 ± 0.32, p < 0.0001; 25.9 ± 13.4 vs. 46.9 ± 16.3%, p < 0.0001, respectively). On the other hand, the ¹²³I-MIBG WR was not correlated with LVEF and had a weak correlation with plasma BNP levels (R = 0.207, p = 0.0346). Moreover, patients with a high ¹²³I-MIBG WR showed a poor clinical outcome (p = 0.0033).

Conclusions

¹²³I-MIBG imaging provides independent prognostic information in patients with HFPEF.     

Correlation between severity of pulmonary arterial hypertension and 123I-metaiodobenzylguanidine left ventricular imaging.

It remains unclear whether cardiac sympathetic nervous function is disturbed in patients with pulmonary arterial hypertension (PH) and how sympathetic dysfunction is related to PH. METHODS: In this study, (123)I-metaiodobenzylguanidine (MIBG) imaging of the heart, which reveals the sympathetic innervation of the left ventricle, was performed in 7 healthy volunteers without cardiopulmonary disease (control subjects); 55 patients with PH, including 27 with chronic thromboembolic pulmonary hypertension (CTEPH) of major vessels; and 28 patients with primary pulmonary hypertension (PPH). RESULTS: Cardiac (123)I-MIBG uptake, assessed as the heart-to-mediastinum activity ratio (H/M), was significantly lower in the CTEPH and PPH groups compared with that in the control group (P < 0.01). Myocardial MIBG turnover, expressed as the washout rate (WR [%]) from 15 to 240 min, was significantly higher in the CTEPH and PPH groups than that in the control group (P < 0.01). In the PPH group, H/M and WR values of MIBG correlated with the severity of pulmonary hypertension (represented by total pulmonary vascular resistance determined by right heart catheterization), the right ventricular ejection fraction determined by electron beam CT, and other variables but did not correlate well in the CTEPH group. In both groups, patients with H/M > or = 2.0 showed better cumulative survival than did those with H/M < 2.0 (P < 0.05). CONCLUSION: Patients with PH have significant left ventricular myocardial sympathetic nervous alteration. (123)I-MIBG imaging of the heart is useful for assessing the severity of pulmonary hypertension caused by PPH or CTEPH.     

Clinical usefulness of a dual L/N-type Ca2+ channel blocker, cilnidipine, in patients with chronic heart failure: assessment with 123I-MIBG myocardial scintigraphy

Sympathetic nerve system is activated as a compensatory mechanism in heart failure. However, excessive activation of sympathetic nerve system deteriorates disease state. Sympathetic nerve system can be suppressed with N-type Ca2+ channel blocker. An antihypertensive drug, cilnidipine, is a dual L/N-type Ca2+ channel blocker. We studies usefulness of cilnidipine in treating with chronic heart failure with 123I-MIBG myocardial scintigraphy. We enrolled 24 patients with stable chronic heart failure. Twelve patients were treated with ACE-inhibitors, diuretics and cardiotonics (control group), and the other 12 patients were treated with ACE-inhibitors, diuretics, cardiotonics and cilnidipine (cilnidipine group). We examined blood pressure, heart rate, norepinephrine level, brain natriuretic peptide (BNP) level, cardiothoracic ratio on chest X-ray, ejection fraction of left ventricle on two-dimensional echocardiography, count rate of heart to mediastinum (H/M) and washout rate (WOR) on 123I-MIBG myocardial scintigraphy before and six months after medication. Symptom was improved in 8 patients in the control group and 10 patients in the cilnidipine group after medication. And another parameters were also improved in the both groups after medication. However the degree of change in blood pressure (mmHg) was 21.2 +/- 8.0 in the cilnidipine group and 10.8 +/- 9.1 in the control group, that in heart rate (/min) was 24.1 +/- 6.8 and 16.2 +/- 11.0, that in BNP level (pg/ml) was 65.2 +/- 12.0 and 42.8 +/- 11.1, that in H/M was 0.30 +/- 0.08 and 0.19 +/- 0.09, that in WOR was 19.4 +/- 5.6 and 12.2 +/- 7.0, respectively. And the degree of these changes were larger in the cilnidipine group (p < 0.05). These findings suggested that cilnidipine, a dual L/N-type Ca2+ channel blocker, might be useful in treating with chronic heart failure.     

Predicting the need for an implantable cardioverter defibrillator using cardiac metaiodobenzylguanidine activity together with plasma natriuretic peptide concentration or left ventricular function.

Despite widespread use of implantable cardioverter defibrillators (ICDs), their cost and the fact that only a certain group of patients fully benefits from the devices require appropriate risk stratification of patients. This study investigated whether altered cardiac autonomic function is associated with the occurrence of ICD discharge or lethal cardiac events. METHODS: Fifty-four ICD-treated patients were prospectively followed after assessment of cardiac metaiodobenzylguanidine (MIBG) activity, quantified as the heart-to-mediastinum ratio (HMR), plasma concentration of brain natriuretic peptide (BNP), and left ventricular ejection fraction (LVEF). Patients were divided into 2 groups based on the presence (group A, n = 21) or absence (group B, n = 33) of appropriate ICD discharge during a 15-mo period. RESULTS: Group A had a significantly lower level of MIBG activity and a higher plasma BNP level than did group B. Univariate analysis revealed BNP level, any medication, and late HMR to be significant predictors, and multivariate analysis showed late HMR to be an independent predictor. An HMR of less than 1.95 with a plasma BNP level of more than 187 pg/mL or an LVEF of less than 50% had significantly increased power to predict ICD shock: positive predictive values, 82% (HMR + BNP) and 58% (HMR + LVEF); negative predictive values, 73% (HMR + BNP) and 77% (HMR + LVEF); sensitivities, 45% (HMR + BNP) and 67% (HMR + LVEF); and specificities, 94% (HMR + BNP) and 70% (HMR + LVEF). CONCLUSION: When combined with plasma BNP concentration or cardiac function, cardiac MIBG activity is closely related to lethal cardiac events and can be used to identify patients who would benefit most from an ICD.     

Prognostic value of MIBG imaging in idiopathic dilated cardiomyopathy.

Alterations of cardiac sympathetic innervation are likely to contribute to fatal outcomes in patients with heart failure. These alterations can be evaluated noninvasively by 123I-metaiodoben-zylguanidine (MIBG) imaging. METHODS: The hypothesis that impaired cardiac sympathetic innervation, as assessed using MIBG imaging, is related to adverse outcomes was tested in 112 patients with heart failure resulting from idiopathic cardiomyopathy. Main inclusion criteria were New York Heart Association classes II-IV and radionuclide left ventricular ejection fraction (LVEF) < 40%. Patients were assessed for cardiac MIBG uptake, circulating norepinephrine concentration, LVEF, peak Vo2, x-ray cardiothoracic ratio, M-mode echographic end-diastolic diameter and right-sided heart catheterization parameters. RESULTS: During a mean follow-up of 27 +/- 20 mo, 19 patients had transplants, 25 died of cardiac death (8 sudden deaths), 2 died of noncardiac death and 66 survived without transplantation. The only independent predictors for mortality were low MIBG uptake (P < 0.001) and LVEF (P = 0.02) when using multivariate discriminant analysis. Moreover, MIBG uptake (P < 0.001) and circulating norepinephrine concentration (P = 0.001) were the only independent predictors for life duration when using multivariate life table analysis. CONCLUSION: Impaired cardiac adrenergic innervation as assessed by MIBG imaging is strongly related to mortality. MIBG imaging may help risk stratify patients with heart failure resulting from idiopathic dilated cardiomyopathy.