Cardiac Sympathetic Nerve Function Research Articles

Cardiac Sympathetic Denervation and Ongoing Myocardial Damage for Prognosis in Early Stages of Heart Failure

Iodine-123-metaiodobenzylguanidine ((123)I-MIBG) can assess cardiac sympathetic nervous function. Heart-type fatty acid binding protein (H-FABP) has been used as a marker of ongoing myocardial damage. The prognostic value of combination (123)I-MIBG imaging and H-FABP in heart failure is unknown. We prospectively enrolled consecutive 104 patients with heart failure in whom we quantified (123)I-MIBG scintigraphy, simultaneously measured serum H-FABP and plasma brain natriuretic peptide (BNP) levels, and analyzed clinical outcomes. The multivariate Cox regression analysis revealed that augmented H-FABP level and decreased heart to mediastinum ratio of (123)I-MIBG at 240 minutes (delayed H/M ratio), but not BNP, were the independent predictors for cardiac events. The cutoff values for H-FABP and delayed H/M ratio were determined from the receiver operating characteristic curves as 5.2 ng/mL for H-FABP and 1.73 for delayed H/M ratio. The cardiac event rate was markedly higher in patients with both H-FABP and delayed H/M ratio of (123)I-MIBG was abnormal. Conversely, no cardiac events occurred in patients with both H-FABP level and delayed H/M ratio were normal. H-FABP adds independent prognostic information to delayed H/M ratio of (123)I-MIBG imaging, and the combination of these approaches may improve the accuracy of prognostic determination in heart failure.

Importance of renal function on prognostic value of cardiac iodine-123 metaiodobenzylguanidine scintigraphy

Cardiac iodine-123 metaiodobenzylguanidine (MIBG) can be used to evaluate cardiac sympathetic nerve function and is useful for assessing the prognosis of patients with heart disease. Renal impairment in heart failure patients has been recognized as an independent risk factor for morbidity and mortality, and has been observed as abnormal uptake and washout of cardiac MIBG imaging. The purpose of this study was to evaluate the prognostic value of cardiac MIBG imaging in heart disease patients with a glomerular filtration rate (GFR) either > or = 60 ml/min/1.73 m2 or < 60 ml/min/1.73 m2. Heart disease patients (n: 135, male/female: 87/48, mean age: 63 years, coronary artery disease/dilated cardiomyopathy/myocarditis: 41/62/32, mean left ventricular ejection fraction: 51%, GFR > or = 60 ml/min/1.73 m2/ GFR < 60 ml/min/1.73 m2: 103/32) underwent cardiac MIBG imaging and were followed-up for 2.7 years. GFR was calculated by the Modification of Diet in Renal Disease (MDRD) equation. Cardiac MIBG imaging was obtained 15 min and 4 h after isotope injection. The parameters analyzed for cardiac MIBG imaging were the heart-to-mediastinum ratio (H/M) on the delayed planar image and the cardiac washout rate. Cardiac death was observed in 9 of 103 patients (9%) with a GFR > or = 60 ml/min/1.73 m2 and in 6 of 32 patients (19%) with a GFR < 60 ml/min/1.73 m2. The mortality ratio tended to be higher in patients with a GFR < 60 ml/min/1.73 m2 than in patients with a GFR > or = 60 ml/min/1.73 m2 (p = 0.10 with Kaplan-Meier survival curves). In patients with a GFR > or = 60 ml/min/1.73 m2, Cox regression analysis showed that a delayed H/M < 146% was the most powerful predictor for cardiac death (Hazard ratio: 6.9, p = 0.014). However, in patients with a GFR < 60 ml/min/1.73 m2, the utility of cardiac MIBG imaging could not be proved. A delayed H/M is a powerful predictor of cardiac death if the GFR is 60 ml/min/1.73 m2 or more.

Scintigraphic Evaluation of Cardiac Metabolism and Sympathetic Nerve Function in Alcoholic Cardiomyopathy

A 70-year-old man with alcoholic cardiomyopathy underwent 99mtechnetium-sestamibi (MIBI), iodine-123-labeled metaiodobenzylguanidine (MIBG) scintigraphy and Iodine-123-labeled beta-methyl-iodophenyl pentadecanoic acid (BMIPP) scintigraphy. 99mtechnetium-MIBI identified myocardial damage in the inferior wall of left ventricle. (123)I BMIPP showed low uptake in the inferior wall of the myocardium, concordant to perfusion. (123)I BMIPP and (123)I MIBG showed reduced uptake in the inferior segment of the myocardium, indicating impairment of fatty acid metabolism and sympathetic abnormalities. Damaged myocardium was demonstrated in alcoholic cardiomyopathy. Beta blocker (carvedilol) and angiotensin-receptor blocker (valsartan) were started at low doses, then increased gradually, leading to the improvement of cardiac performance. Cardiac sympathetic nerve function, impaired due to alcoholic cardiomyopathy, was improved with beta-blocker therapy. Cardiac scintigraphy may be useful to assess the extent of myocardial improvement and the response to therapy.

Cardiac Sympathetic Dysfunction Correlates With Abnormal Myocardial Contractile Reserve in Dilated Cardiomyopathy Patients

We investigated the relationship between iodine-123-metaiodobenzylguanidine (123I-MIBG) findings and myocardial contractile reserve in patients with mild to moderate dilated cardiomyopathy (DCM). Little is known regarding the relationship between cardiac sympathetic nervous function and myocardial contractile reserve in DCM. Twenty-four DCM patients who showed sinus rhythm underwent echocardiography, biventricular catheterization, and myocardial 123I-MIBG scintigraphy. Left ventricular (LV) pressures were measured using a micromanometer-tipped catheter. The myocardial contractile function (LV dP/dt(max)) was determined at rest and during atrial pacing. The messenger ribonucleic acid (mRNA) expressions of intracellular Ca2+-regulatory proteins were analyzed by real-time quantitative reverse transcription-polymerase chain reaction. Myocardial 123I-MIBG accumulation was quantified as a heart-mediastinum ratio (HMR). A significant correlation was observed between the delayed 123I-MIBG HMR and the percentage change in LV dP/dt(max) from the baseline to the peak or critical heart rate (r = 0.64; p < 0.001). The delayed 123I-MIBG HMR was significantly lower in patients showing a worsening change in LV dP/dt(max) than in those showing a favorable change (p < 0.005). The maximum LV dP/dt(max) during pacing and the sarcoplasmic reticulum Ca2+-ATPase (SERCA2) mRNA levels were significantly more reduced in patients with a delayed HMR < or =1.8 than in those with a delayed HMR >1.8 (p < 0.05, respectively). Abnormal myocardial 123I-MIBG accumulation is related to an impaired myocardial contractile reserve and down-regulation of SERCA2 mRNA in DCM. Myocardial 123I-MIBG scintigraphy can be useful in noninvasively evaluating myocardial contractile reserve in patients with mild to moderate DCM.

Influence of the polyol pathway on norepinephrine transporter reduction in diabetic cardiac sympathetic nerves: implications for heterogeneous accumulation of MIBG

Cardiac scintigraphic studies using 123I-labeled metaiodobenzylguanidine ([123I]MIBG) have demonstrated heterogeneous myocardial accumulation of MIBG in diabetes. The accumulation has been found to correlate with a heterogeneous decrease in the expression of norepinephrine transporter (NET). In diabetic peripheral nerve tissue, polyol pathways are activated and cause nerve dysfunction and degeneration. However, there has been little research on the polyol pathway and cardiac sympathetic nerves. Therefore, to assess the influence of the polyol pathway on cardiac sympathetic nervous function, we investigated the regional accumulation of MIBG and NET protein expression in diabetic model rats treated with aldose reductase inhibitor (ARI) for the blockade of polyol pathways. Rats were given a single intravenous injection of streptozotocin (n=76, STZ-D rats). Starting the day after STZ injection, ARI was administered daily to 42 of the rats for 4 weeks (ARI-D rats). To assess the cardiac sympathetic nervous function, [125I]MIBG autoradiographic experiments were carried out. Finally, NET protein expression was assessed with a saturation binding assay. The myocardial sorbitol concentration was significantly higher in STZ-D rats than in ARI-D rats. There was no heterogeneous accumulation of MIBG in ARI-D rats. There was a heterogeneous decrease of NET expression in STZ-D rats, but not in ARI-D or control rats. The gathered data indicate that the enhanced polyol pathway correlates with the decrease in regional cardiac sympathetic nervous function, and this impairment may lead to the reduction of NET protein in cardiac sympathetic nerves of the diabetic inferior wall.

Sympathetic neuronal regulation of the heart in aging and heart failure

The documentation of preferential activation of the cardiac sympathetic outflow in patients with heart failure swept aside an entrenched notion that there was a functional sympathetic denervation of the failing heart and provided a theoretical basis for the clinical evaluation of beta-adrenergic blocker therapy in this condition. The demonstration that heightened sympathetic nervous system activity is central to the pathogenesis and progression of congestive heart failure (CHF) has now led to the rational use of beta-adrenoceptor blockade in CHF. More recently, it has also emerged that the aging heart exhibits some of the characteristic changes in autonomic control which are seen in CHF. Accordingly, alterations in cardiac sympathetic nerve function are now thought to contribute also to the pathophysiology of the aging heart. Furthermore, there is evidence that in humans, sympathoexcitatory rostral projections of brainstem noradrenergic neurons to the forebrain are important in the sympathetic nervous activation of both heart failure and aging. Given these similarities, in this review we compare and contrast the neurobiology of the sympathetic nervous system in the failing heart and the healthy, aging heart, and consider whether the sympathetic activation accompanying aging may, perhaps, underlie and contribute to the neural pathophysiology of heart failure. Our conclusion is, on balance, that this proposition is not supported by the available evidence.

The effect of β-adrenergic receptor antagonism in cardiac sympathetic neuronal remodeling in patients with heart failure

Background β-adrenergic receptor antagonism with drugs like carvedilol slows the progression of heart failure by an undefined mechanism. 123I-metaiodobenzylguanidine (MIBG) is an analog of norepinephrine used to study cardiac sympathetic function. Methods and results In this double-blind randomized, placebo-controlled study, we used MIBG imaging to evaluate the effect of carvedilol ( n = 15) or placebo ( n = 7) on neuronal norepinephrine reuptake in patients with heart failure due to idiopathic dilated cardiomyopathy, with LVEF less than 35% and functional class II or III. The drug was begun at 6.25 mg b.i.d. and titrated up to 25 mg t.i.d, as tolerated. Thorax planar scintigraphy images were obtained 15 min (Initial) and 4 h (Late) after MIBG injection at baseline ( t 0) as well as 2 months ( t 1) and 6 months ( t 2) after drug initiation. The multifarious statistical technique of profile analysis was applied and p ≤ 0.05 was considered significant. The heart/mediastinum MIBG uptake (H/M ratio) was calculated from these images. On the Initial images, the H/M ratio was 1.64 ± 0.24 ( t 0), 1.71 ± 0.21 ( t 1), and 1.87 ± 0.34 ( t 2) in the carvedilol group and 1.68 ± 0.42 ( t 0), 1.81 ± 0.45 ( t 1), and 1.69 ± 0.44 ( t 2) in controls ( p = 0.0455). On the Late images, the H/M ratio was 1.39 ± 0.24 ( t 0), 1.53 ± 0.23 ( t 1), and 1.64 ± 0.36 ( t 2) in the carvedilol group, and 1.49 ± 0.45 ( t 0), 1.53 ± 0.47 ( t 1), and 1.47 ± 0.41 ( t 2) in controls ( p = 0.0513). Conclusion Compared with placebo, the addition of carvedilol to existing heart failure treatment incites the reverse remodeling of cardiac sympathetic nervous system function.

Extension of myocardial necrosis differently affects MIBG retention in heart failure caused by ischaemic heart disease or by dilated cardiomyopathy

This study aims to investigate the relationship between cardiac sympathetic nervous function (CSNF) and myocardial perfusion/function in patients with heart failure (HF) due to dilated cardiomyopathy (DCM) or ischaemic heart disease (CAD). Twenty patients (10 DCM, 10 CAD, 17 males, age 69+/-5 years) with NYHA class IIIb HF were studied. CSNF was evaluated by early/delayed (123)I-metaiodobenzylguanidine (MIBG) uptake and regional washout (WO). Myocardial perfusion and function were evaluated by (99m)Tc-tetrofosmin gated single-photon emission tomography (G-SPECT) using a 20-segment model for 400 segments. In each segment, regional MIBG WO was computed as (count density in early images-count density in delayed images/count density in early images)x100. DCM and CAD showed similar summed rest perfusion score (6.7+/-5 vs 9.5+/-5, p=NS) and mean ejection fraction values (29+/-7% vs 30+/-9%, p=NS). By contrast, the summed thickening score was higher in DCM than in CAD patients (26+/-7 vs 17+/-6, p<0.05). QGS analysis identified akinesis/dyskinesis in 129/137 (94%) severely hypoperfused segments which were considered as damaged. According to the underlying aetiology of HF, marked differences in regional MIBG WO were observed. In fact, within the CAD group, regional MIBG WO was lower in reference than in damaged segments (38+/-21% vs 46+/-19%, p<0.05). By contrast, in DCM patients, regional MIBG WO was faster in reference than in damaged segments (49+/-18% vs 41+/-30%, p<0.05). When the two groups were directly compared, regional MIBG WO from damaged areas was similar irrespective of the underlying disease, while it was faster in DCM than in CAD patients from reference segments. These data confirm the hypothesis that the presence of myocardial necrosis in HF due to CAD and the consequent loss of neuronal endings cause alterations in regional MIBG WO different from those observed in DCM.

Impaired Cardiac Sympathetic Nerve Function in Patients with Kawasaki Disease: Comparison with Myocardial Perfusion

Kawasaki disease (KD) is a leading cause of CAD in children. The impairment of cardiac sympathetic nerve function (CSNF) in the adult patients with coronary artery disease (CAD) could often be seen. However, little is known concerning the impairment of CSNF in KD patients. We investigated CSNF and its relationship with myocardial perfusion in KD patients. Eleven children with KD and 4 controls were studied with 123I-metaiodobenzylguanidine (MIBG) and stressed 201Tl single photon emission computed tomography. By the findings on coronary artery angiography (CAG), the patients were divided into 2 groups: A, without stenosis; B, with significant stenosis and/or old myocardial infarction. CSNF was evaluated from the uptake of 123I-MIBG. While myocardial perfusion was evaluated from 201Tl uptake. The numbers of patients in the groups A and B were 7 and 4. Perfusion defect was found in 0, and 2 patients in group A (0%), and B (50%). 123I-MIBG defects were found in 1 and 4 patients in the group A (14%) and B (100%). There were excellent concordances between the finding of 201Tl and 123I-MIBG in group A. While in group B, the coronary territories with 123I-MIBG defects were significantly more than those with perfusion defects (p < 0.05). In KD patients, the impairment of CSNF might be subsequent to coronary artery stenosis and was more severe than the injury of myocardial perfusion.

Amiodarone Improves Cardiac Sympathetic Nerve Function to Hold Norepinephrine in the Heart, Prevents Left Ventricular Remodeling, and Improves Cardiac Function in Rat Dilated Cardiomyopathy

It is unclear how amiodarone therapy exerts its effects on left ventricular remodeling and cardiac sympathetic nerve function in chronic heart failure. We investigated long-term effects of amiodarone on rat dilated cardiomyopathy after healing of cardiac myosin-induced autoimmune myocarditis. Rats were treated with oral amiodarone or vehicle for 6 weeks. We determined cardiac function, left ventricular remodeling, and cardiac sympathetic nerve function with iodine-125-labeled metaiodobenzylguanidine ([I125]MIBG). Amiodarone treatment improved left ventricular pressure, central venous pressure, and rate of isovolumetric contraction and decreased ventricular weight (P<0.005). Expression of cytokine mRNA was unchanged; expression of atrial natriuretic peptide, collagen III, and transforming growth factor-beta1 mRNA was decreased in amiodarone-treated rats (P<0.05). Phenotype of myosin heavy chain was moved toward that of normal rats by amiodarone. Initial myocardial uptake of MIBG decreased by 67% (P<0.001) and washout rate accelerated by 221% in rats with chronic heart failure compared with normal rats. Whereas amiodarone decreased the initial uptake by 71% in normal rats, amiodarone decelerated the early washout and the late washout and improved the late myocardial distribution of MIBG in rats with chronic heart failure (257% compared with vehicle-treated rats with chronic heart failure; P<0.01). In proportion to MIBG distributions, cardiac tissue catecholamines were increased by amiodarone treatment. Long-term amiodarone treatment prevented left ventricular remodeling and improved cardiac function in rat dilated cardiomyopathy. Long-term amiodarone treatment also restored cardiac sympathetic tone to hold norepinephrine in the heart.

Influence of the polyol pathway on norepinephrine transporter reduction in diabetic cardiac sympathetic nerves: implications for heterogeneous accumulation of MIBG

Cardiac scintigraphic studies using (123)I-labeled metaiodobenzylguanidine ([(123)I]MIBG) have demonstrated heterogeneous myocardial accumulation of MIBG in diabetes. The accumulation has been found to correlate with a heterogeneous decrease in the expression of norepinephrine transporter (NET). In diabetic peripheral nerve tissue, polyol pathways are activated and cause nerve dysfunction and degeneration. However, there has been little research on the polyol pathway and cardiac sympathetic nerves. Therefore, to assess the influence of the polyol pathway on cardiac sympathetic nervous function, we investigated the regional accumulation of MIBG and NET protein expression in diabetic model rats treated with aldose reductase inhibitor (ARI) for the blockade of polyol pathways. Rats were given a single intravenous injection of streptozotocin (n=76, STZ-D rats). Starting the day after STZ injection, ARI was administered daily to 42 of the rats for 4 weeks (ARI-D rats). To assess the cardiac sympathetic nervous function, [(125)I]MIBG autoradiographic experiments were carried out. Finally, NET protein expression was assessed with a saturation binding assay. The myocardial sorbitol concentration was significantly higher in STZ-D rats than in ARI-D rats. There was no heterogeneous accumulation of MIBG in ARI-D rats. There was a heterogeneous decrease of NET expression in STZ-D rats, but not in ARI-D or control rats. The gathered data indicate that the enhanced polyol pathway correlates with the decrease in regional cardiac sympathetic nervous function, and this impairment may lead to the reduction of NET protein in cardiac sympathetic nerves of the diabetic inferior wall.

Dietary cholesterol affects sympathetic nerve function in rabbit hearts.

In order to assess the effect of hypercholesterolemia on cardiac sympathetic nerve function, New Zealand white rabbits were fed a normal diet (the control group) or one enriched with 0.5% cholesterol [the hypercholesterol (HC) group] for 3 months. Before and after the 3-month diet treatment, we performed serial imaging examinations and analyzed the uptake and washout ratio of (123)I-meta-iodobenzylguanidine ((123)I-MIBG) from the myocardium by administration of (123)I-MIBG through an ear vein. At the end of the experiments, the rabbits were sacrificed, and right ventricular strips were taken from their hearts. The inotropic response of the right ventricular strips to isoproterenol (ISO) and norepinephrine (NE) were evaluated. The cardiac MIBG uptake of the HC group, which was evaluated using the heart to mediastinum ratio, was higher than that of the age-matched control group. However, the washout ratios of (123)I-MIBG did not differ statistically between the two groups. On pretreatment with cocaine, NE-enhanced contractility was greater in papillary muscles isolated from the HC group. The concentration-response curve to ISO was shifted to the right in the HC group, compared with that in the control group. In conclusion, hypercholesterolemia in rabbits resulted in an increase in sympathetic nerve density in the myocardium, a decrease in the inotropic response to ISO and an increase in the inotropic response to NE in cocaine-treated myocardium. Both the in vivo and in vitro studies demonstrated the functional significance of neural remodeling induced by hypercholesterolemia.

Dietary Cholesterol Affects Sympathetic Nerve Function in Rabbit Hearts

In order to assess the effect of hypercholesterolemia on cardiac sympathetic nerve function, New Zealand white rabbits were fed a normal diet (the control group) or one enriched with 0.5% cholesterol [the hypercholesterol (HC) group] for 3 months. Before and after the 3-month diet treatment, we performed serial imaging examinations and analyzed the uptake and washout ratio of ¹²³I-meta-iodobenzylguanidine (¹²³I-MIBG) from the myocardium by administration of ¹²³I-MIBG through an ear vein. At the end of the experiments, the rabbits were sacrificed, and right ventricular strips were taken from their hearts. The inotropic response of the right ventricular strips to isoproterenol (ISO) and norepinephrine (NE) were evaluated. The cardiac MIBG uptake of the HC group, which was evaluated using the heart to mediastinum ratio, was higher than that of the age-matched control group. However, the washout ratios of ¹²³I-MIBG did not differ statistically between the two groups. On pretreatment with cocaine, NE-enhanced contractility was greater in papillary muscles isolated from the HC group. The concentration-response curve to ISO was shifted to the right in the HC group, compared with that in the control group. In conclusion, hypercholesterolemia in rabbits resulted in an increase in sympathetic nerve density in the myocardium, a decrease in the inotropic response to ISO and an increase in the inotropic response to NE in cocaine-treated myocardium. Both the in vivo and in vitro studies demonstrated the functional significance of neural remodeling induced by hypercholesterolemia.

Evaluation of cardiac sympathetic nerve function by myocardial 123I-metaiodobenzylguanidine scintigraphy before and after endoscopic sympathectomy.

The purpose of this study was to analyze the change in cardiac sympathetic function by performing a 123I-metaiodobenzylguanidine (MIBG) imaging study after endoscopic upper thoracic sympathectomy (EUTS) in patients with palmar hyperhidrosis before and after surgery. Between February 1999 and February 2002, 135 patients underwent bilateral EUTS to treat palmar hyperhidrosis. Between September 2001 and February 2002, 12 of these consecutively enrolled patients were also included in a 123I-MIBG imaging study. These patients underwent cardiac 123I-MIBG imaging 1 day before and 7 days after they had undergone EUTS. The heart/mediastinum (H/M) ratio and the washout rate were calculated for both early and late phases, and single-photon emission computerized tomography (SPECT) imaging of the early phase was performed. Excessive perspiration from the palms disappeared immediately after EUTS in all patients, and they showed no symptoms of a circulatory condition following the procedure. On the 123I-MIBG imaging studies, the early H/M ratio before EUTS was 2.35 +/- 0.26 and postoperatively it was 2.29 +/- 0.23. The delayed H/M ratio before EUTS was 2.59 +/- 0.3 and after the procedure it was 2.66 +/- 0.27. There was no significant difference between the H/M ratio before and after EUTS. The washout rate after EUTS (14.27 +/- 4.71%) was significantly lower than that measured before EUTS (18.36 +/- 5.13%: p < 0.01). No apparent local defects of accumulation of MIBG were found on SPECT images obtained post-EUTS. Endoscopic upper thoracic sympathectomy is a minimally invasive procedure; no local denervation was found after EUTS. Findings on 123I-MIBG imaging studies indicate that EUTS suppresses the activation of the sympathetic nervous system slightly, similar to beta-blocker therapy.

Effect of collimator choice on quantitative assessment of cardiac iodine 123 MIBG uptake

Background Quantitative accuracy in iodine 123 studies may be impaired by septal penetration. We evaluated the effect of collimator choice on estimation of the heart-to-mediastinum (H/M) ratio in cardiac I-123 metaiodobenzylguanidine (MIBG) imaging. Methods and results A low-energy high-resolution (LEHR) collimator, special LEHR (SLEHR) collimator, and medium-energy (ME) collimator were used. In experiments in which a phantom of simple geometry was used, the use of the LEHR collimator provided the lowest contrast accuracy, suggesting the effect of septal penetration. Thoracic phantom studies demonstrated contamination of heart and mediastinum counts by lung and liver activities, which was greatest with the LEHR collimator and least with the ME collimator. In 8 patients anterior chest views were acquired successively with the three collimators after I-123 MIBG injection. H/M ratios were significantly higher with the SLEHR collimator than with the LEHR collimator and were still higher with the ME collimator. The difference in H/M ratios between the LEHR and ME collimators showed a high positive correlation with the lung-to-mediastinum ratio. Conclusions Collimator choice substantially influences estimation of the H/M ratios in cardiac I-123 MIBG imaging. The use of an ME collimator provides high quantitative accuracy and may enhance reliability in the evaluation of cardiac sympathetic nerve function.

Carvedilol improves left ventricular function in heart failure patients with idiopathic dilated cardiomyopathy and a wide range of sympathetic nervous system function as measured by iodine 123 metaiodobenzylguanidine

Background. Carvedilol treatment reduces the mortality rate in patients with congestive heart failure. It is not known whether carvedilol treatment is effective in heart failure patients with substantial cardiac sympathetic nerve dysfunction. The goal of this study was to determine the effect of chronic carvedilol treatment in patients with cardiac sympathetic nerve dysfunction of varying severity. Methods and Results. In 22 congestive heart failure patients with idiopathic cardiomyopathy, sympathetic nerve function was assessed before and after 7.2 ± 2.7 months of carvedilol treatment with the use of iodine 123 metaiodobenzylguanidine (MIBG) imaging, radionuclide ventriculography, and transmyocardial norepinephrine sampling. Patients with relatively advanced impairment of cardiac sympathetic nerve function, as manifested by a baseline I-123 MIBG ratio lower than 1.40, had a statistically significant improvement in I-123 heart-mediastinum ratio with carvedilol treatment, from 1.26 ± 0.12 to 1.39 ± 0.20 ( P = .004). Of 10 patients with a baseline I-123 MIBG ratio lower than 1.40, 9 had an increase in the heart-mediastinum ratio with carvedilol treatment. Left ventricular ejection fraction increased from 25.4% ± 7.8% to 37.3% ± 14.7% ( P < .001), with no difference between patients with relatively advanced versus relatively preserved cardiac sympathetic nerve function. Conclusions. Most patients with congestive heart failure show a favorable response in left ventricular function to carvedilol treatment, regardless of the baseline level of cardiac sympathetic nervous system function, as assessed by neuronal imaging with I-123 MIBG. Patients with relatively advanced impairment of baseline I-123 MIBG uptake are most likely to show evidence of improved cardiac sympathetic nervous system function in response to carvedilol therapy. (J Nucl Cardiol 2002;9:608-15)

Iodine-123 metaiodobenzylguanidine scintigraphic analysis of myocardial sympathetic innervation in patients with AL (primary) amyloidosis

Background Although a high incidence of myocardial adrenergic denervation has been reported in patients with familial amyloid polyneuropathy, assessment of cardiac sympathetic nerve function has not been available in patients with AL (primary) amyloidosis. Methods To test the hypothesis that myocardial sympathetic nerve innervation might be impaired and variable according to the presence or absence of clinical autonomic abnormalities and congestive heart failure in AL amyloidosis, we examined 25 patients by use of iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy. Results Ten of the 16 patients without autonomic symptoms and 5 of the 9 patients with autonomic neuropathy showed congestive heart failure. The heart/mediastinal activity (H/M) ratio (1.53 ± 0.06 vs 1.29 ± 0.05 at 3 hours, P <.001) and myocardial washout ratio (41.5% ± 4.8% vs 30.8% ± 4.0%, P <.001) of MIBG were significantly increased in patients without autonomic symptoms compared with patients showing autonomic neuropathy. In patient groups with and without autonomic dysfunction, patients demonstrating congestive heart failure exhibited a significantly decreased H/M ratio and increased washout compared with patients with no heart failure, and left ventricular fractional shortening was positively correlated with the H/M ratio and inversely correlated with the washout ratio. There were significant correlations between the low-frequency component of the heart rate variability and the H/M ratio and washout ratio in the entire patient population. Conclusions Patients with AL amyloidosis and no autonomic dysfunction showed variable degrees of enhanced cardiac adrenergic neuronal activity with presynaptic sympathetic dysfunction. In contrast, patients with AL amyloidosis and autonomic neuropathy exhibited prominent myocardial adrenergic denervation with normal or impaired sympathetic neural function of the heart. This study demonstrates that myocardial uptake and turnover of MIBG in patients with AL amyloidosis are heterogeneous and dependent on the presence or absence of congestive heart failure and cardiac autonomic dysfunction. (Am Heart J 2002;144:122-9.)

Cardiac sympathetic denervationmodulates the sympathoexcitatoryresponse to acute myocardial ischemia

ObjectivesThis study was designed to elucidate the influence of cardiac sympathetic denervation on the sympathoexcitatory response to acute myocardial ischemia during balloon coronary occlusion (BCO) in humans. BackgroundAlterations of cardiac sympathetic nerve function could modulate sympathetic reflexes originating from the ischemic area. MethodsIn 23 patients with angina pectoris, we quantified the baseline cardiac sympathetic denervation of the ischemia-related area by iodine-123 metaiodobenzylguanidine (123I-MIBG), and transient changes in sympathetic activity during BCO by wavelet analysis of RR interval variability. ResultsBalloon coronary occlusion resulted in a transient augmentation of low-frequency (LF: 0.04 to 0.14 Hz) spectral components of RR interval variability in 4 of 12 patients with cardiac denervation and in 8 of 11 patients without denervation (p < 0.01 by the chi-square test). Consequently, the increase in LF components was significantly less during BCO in patients with cardiac denervation (34%) than in those without denervation (273%) (interaction: p < 0.05). In seven patients with severe ischemia provoked by a fall of ≥10% in the left ventricular ejection fraction, LF components increased by 506% during BCO, regardless of the condition of cardiac denervation. In contrast, in patients with mild ischemia provoked by a fall of <10% in the ejection fraction, changes of LF components during BCO were significantly less in patients with denervation than in those without denervation (84 vs. 344%, p < 0.05). ConclusionsThese findings suggest that if the provoked ischemia is not severe, cardiac sympathetic denervation could prevent ischemia-induced sympathoexcitation.

Relationship between cardiac sympathetic function and baroreceptor sensitivity after acute myocardial infarction.

The relationship between baroreceptor sensitivity (BRS) and cardiac sympathetic nerve function after acute myocardial infarction (AMI) was investigated in 34 patients. BRS was measured during the Valsalva maneuver and cardiac sympathetic function was assessed by the washout rate (WR) of I-123 meta-iodo-benzyl guanidine (123I-MIBG) with planar image (global WR) and polar map analysis (regional WR). Gated left ventricular ejection fraction (LVEF) measured by left ventriculography as a parameter of ventricular function was measured with quantitative gated SPECT (QGS). The gated LVEF correlated with global WR (r=-0.36, p=0.034) and regional WR of normal area (r=-0.46, p=0.006), but not with BRS, although BRS correlated with global WR (r=-0.43, p=0.015) and regional WR of normal area (r=-0.72, p<0.0001). After AMI, baroreceptor function is linked to sympathetic activation, as elucidated by the regional WR of normal area, which suggests that separation of the infarcted area from the non-infarcted myocardium is necessary for evaluating sympathetic activation after AMI and that the regional kinetics of 123I-MIBG in the normal area are a more suitable marker of activated cardiac nerve function than global 123I-MIBG kinetics.

Effect of cardiac sympathetic nervous activity on mode of death in congestive heart failure.

To investigate whether strong cardiac sympathetic activity contributes primarily to sudden death or to worsening heart failure, and to determine the relationship of the size of cardiac noradrenaline stores to the mode of death. The study population comprised 116 patients with congestive heart failure (ejection fraction 19+/-7%) and a mean follow-up of 18+/-19 months. Cardiac sympathetic nervous function was measured using coronary sinus blood sampling and noradrenaline isotope dilution methodology. Cardiac sympathetic activity was estimated from cardiac noradrenaline spillover, and noradrenaline stores from the overflow of the tritiated noradrenaline metabolite [(3)H]dihydroxyphenylglycol, which is produced by monoamine oxidase inside nerve endings. Small cardiac noradrenaline stores (below median) predicted death from worsening heart failure (hazard ratio=4.18, P<0.05), particularly if cardiac noradrenaline spillover was elevated (hazard ratio=2.36 per tertile, P<0.01), indicating progression of disease associated with defective sympathetic innervation. In contrast, large stores (hazard ratio=2.81, P<0.05), especially if coupled with increased noradrenaline spillover (hazard ratio=1.64 per tertile, P<0.05), were related to sudden death. High cardiac sympathetic activity is a risk factor for sudden death, particularly in the presence of intact cardiac sympathetic innervation. Conversely, progression of myocardial disease and heart failure is closely associated with depletion of sympathetic nerves in the heart, especially if rates of noradrenaline release paradoxically remain high.