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1.  Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia 
Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function.
Cardiac sympathetic nervous integrity was investigated in vivo via biodistribution of the positron emission tomography radiotracer and NE analogue [11C]meta-hydroxyephedrine ([11C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements.
The animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [11C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle.
Taken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment.
PMCID: PMC3170183  PMID: 21831292
norepinephrine; [11C]meta-hydroxyephedrine (HED); small animal echocardiography; positron emission tomography; diabetes mellitus; cardiovascular disease
2.  123I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson's disease 
OBJECTIVES—123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is clinically used to estimate local myocardial sympathetic nerve damage in some forms of heart disease, autonomic nerve disturbance in diabetic neuropathy, and disturbance of the autonomic nervous system in neurodegenerative disease. In the present study, examinations were performed to clarify (1) the proportion of cardiac sympathetic nerve disturbance in Parkinson's disease, (2) the usefulness of 123I-MIBG myocardial scintigraphy to detect sympathetic nerve disturbances compared with autonomic function tests, (3) cardiac function in patients who have a decreased MIBG uptake in 123I-MIBG myocardial scintigraphy, (4) the usefulness of 123I-MIBG myocardial scintigraphy to differentiate Parkinson's disease from the other neurological diseases mimicking it.
METHODS—123I-MIBG myocardial scintigraphy was performed, together with autonomic function tests and cardiac examinations in 46 patients with Parkinson's disease and 25 patients with vascular parkinsonism, essential tremor, or multiple system atrophy.
RESULTS—In an anterior image study, the average count per pixel in heart to mediastinum (H/M) ratio decreased in 80% of the patients with Parkinson's disease in the early phase and 84% in the late phase. The mean H/M ratio in Parkinson's disease was significantly lower than that in controls and the other diseases. The H/M ratio tended to decrease with the disease progression. In almost half of the patients in Hoehn and Yahr stage I, the H/M ratio was already decreased. The sympathetic skin response in upper and lower limbs, head up tilt test, and coefficient of variation of R-R interval were abnormal in 17%, 31%, 30%, and 17% of the patients, respectively. All the patients with abnormal autonomic functions were in Hoehn and Yahr stage III, IV, or V. Echocardiography showed normal left ventricular function. Twenty four hour Holter electrocardiography detected no serious arrhythmias except for one patient with non-sustained ventricular tachycardia.
CONCLUSION—123I-MIBG myocardial scintigraphy might detect early disturbances of the sympathetic nervous system in Parkinson's disease and might give useful diagnostic information to differentiate vascular parkinsonism, essential tremor, and multiple system atrophy from Parkinson's disease.

PMCID: PMC1736461  PMID: 10406987
3.  Regional patterns of myocardial sympathetic denervation in dilated cardiomyopathy: an analysis using carbon-11 hydroxyephedrine and positron emission tomography 
Heart  1999;81(3):262-270.
OBJECTIVE—To assess presynaptic function of cardiac autonomic innervation in patients with advanced congestive heart failure using positron emission tomography (PET) and the recently developed radiolabelled catecholamine analogue carbon-11 hydroxyephedrine (HED) as a marker for neuronal catecholamine uptake function. 
DESIGN AND PATIENTS—29 patients suffering from dilated cardiomyopathy with moderate to severe heart failure were compared with eight healthy controls. Perfusion scan was followed by HED dynamic PET imaging of cardiac sympathetic innervation. The scintigraphic results were compared with markers of disease severity and the degree of sympathetic dysfunction assessed by means of heart rate variability.
RESULTS—In contrast to nearly normal perfusions, mean (SD) HED retention in dilated cardiomyopathy patients was abnormal in 64 (32)% of the left ventricle. Absolute myocardial HED retention was 10.7 (1.0)%/min in controls v 6.2 (1.6)%/min in dilated cardiomyopathy patients (p < 0.001). Moreover, significant regional reduction of HED retention was demonstrated in apical and inferoapical segments. HED retention was significantly correlated with New York Heart Association functional class (r = −0.55, p = 0.002) and ejection fraction (r = 0.63, p < 0.001), but not, however, with plasma noradrenaline concentrations as well as parameters of heart rate variability. 
CONCLUSIONS—In this study, using PET in combination with HED in patients with dilated cardiomyopathy, not only global reduction but also regional abnormalities of cardiac sympathetic tracer uptake were demonstrated. The degree of abnormality was positively correlated to markers of severity of heart failure. The pathogenetic mechanisms leading to the regional differences of neuronal damage as well as the prognostic significance of these findings remain to be defined.

 Keywords: heart failure; dilated cardiomyopathy; C-11 hydroxyephedrine; positron emission tomography; sympathetic nervous system
PMCID: PMC1728957  PMID: 10026349
4.  Molecular imaging in heart failure patients 
This review focuses on molecular imaging using various radioligands for the tissue characterization of patients with heart failure. 123I-labeled metaiodobenzylguanidine (MIBG), as a marker of adrenergic neuron function, plays an important role in risk stratification in heart failure and may be useful for predicting fatal arrhythmias that may require implantable cardioverter-defibrillator treatment. MIBG has also been used for monitoring treatment effects under various medications. Various positron emission tomography (PET) radioligands have been introduced for the quantitative assessment of presynaptic and postsynaptic neuronal function in vivo. 11C-hydroxyephedrine, like MIBG, has potential for assessing the severity of heart failure. Our PET study using the β-receptor antagonist 11C-CGP 12177 in patients with heart failure showed a reduction of β-receptor density, indicating downregulation, in most of the patients. More studies are needed to confirm the clinical utility of these molecular imaging modalities for the management of heart failure patients.
PMCID: PMC3991005  PMID: 24765617
Radionuclide imaging; Positron emission tomography; Molecular imaging; Heart failure; Adrenergic neuronal imaging; Receptor imaging
5.  Cardiac Resynchronization Therapy Upregulates Cardiac Autonomic Control 
To determine the effect of cardiac resynchronization therapy (CRT) on sympathetic nervous function in heart failure (HF).
Neurohormonal dysregulation and cardiac autonomic dysfunction are associated with HF and contribute to HF progression and its poor prognosis. We hypothesized that mechanical resynchronization improves cardiac sympathetic function in HF.
Sixteen consecutive patients receiving CRT for advanced cardiomyopathy and 10 controls were included in this prospective study. NYHA class, 6-minute walk distance, echocardiographic parameters, plasma norepinephrine (NE) were assessed at baseline, 3-month and 6-month follow-up. Cardiac sympathetic function was determined by 123iodine metaiodobenzylguanidine (123I-MIBG) scintigraphy and 24-hour ambulatory electrocardiography.
Along with improvement in NYHA class (3.1 ± 0.3 to 2.1 ± 0.4, P < 0.001) and LVEF (23 ± 6% to 33 ± 12%, P < 0.001 delayed heart/mediastinum (H/M) 123 I-MIBG ratio increased significantly (1.8 ± 0.7 to 2.1 ± 0.6, P = 0.04) while the H/M 123I-MIBG washout rate decreased significantly (54 ± 25% to 34± 24%, P = 0.01) from baseline to 6-month follow-up. The heart rate variability (HRV) measured in SD of normal-to-normal intervals also increased significantly from baseline (82 ± 30 ms) to follow-up (111 ± 32 ms, P = 0.04). The improvement in NYHA after CRT was significantly associated with baseline 123I-MIBG H/M washout rate (r = 0.65, P = 0.03). The improvement in LVESV index was associated with baseline 123I-MIBG delayed H/M ratio (r = −0.67, P = 0.02) and H/M washout rate (r = 0.65, P = 0.03).
After CRT, improvements in cardiac symptoms and LV function were accompanied by rebalanced cardiac autonomic control as measured by 123I-MIBG and HRV.
PMCID: PMC2756798  PMID: 18479331
cardiac resynchronization therapy; heart failure; cardiomyopathy; ventricular dyssynchrony; sympathetic nerve; 123iodine metaiodobenzylguanidine
6.  Effects of metabolic and myocardial microcirculatory abnormalities on the pathogenesis of cardiac autonomic neuropathy in type 2 diabetes mellitus: A prospective study in Japanese patients* 
In diabetic patients, cardiac autonomic neuropathy is an important factor affecting prognosis. Whether this condition in diabetic patients is caused directly by neurovisceral metabolic disorder and/or indirectly by micro circulation remains to be clarified.
The aim of this study was to determine whether cardiac sympathetic nerve dysfunction can be detected using adenosine triphosphate (ATP) testing, while also investigating the effects of metabolic and/or myocardial microcirculatory abnormalities on the pathogenesis of cardiac autonomic nerve dysfunction in patients with type 2 diabetes mellitus (DM-2) in Japan.
This prospective study was performed at the Division of Diabetology Department of Internal Medicine, Toho University, Ohashi Hospital, Tokyo, Japan. Patients aged ≥ 18 years with DM-2 with no abnormalities on electrocardiography (ECG) or echocardiography were enrolled. An ATP thallium (Tl)-201 myocardial scintigraphy test (ATP test) and iodine (I)-123 metaiodobenzylguanidine (MIBG) scintigraphy were performed. ATP was administered by continuous IV infusion over 6 minutes at 0.16 mg/kg · min. Five minutes after the ATP infusion was started, T1-201 111 MBq IV was administered. Single-photon emission computed tomography (SPECT) imaging was begun immediately after the end of ATP infusion and was completed 3 hours after stress to show washout from stress to rest. I-123 MIBG 111 MBq IV was administered. A planar image from the front side and a SPECT image (early phase) was obtained 15 to 30 minutes later. After 3 hours, a planar image from the front side and a SPECT image (late phase) were obtained to show washout from stress to rest. The mean TI washout rate (ATP-WR) and heart-to-mediastinum (H/M) ratio in the late-phase scintigraphic images and the washout rate of MIBG (MIBG-WR) in the left ventricle was determined. The correlations of these measurements with the mean values of glycosylated hemoglobin (HbA1c) and fasting plasma glucose obtained from monthly measurements over the previous 6 and 24 months were determined.
A total of 25 patients were enrolled (13 men, 12 women; mean [SD] age, 59.86 [8.28] years). Significant negative correlations between both ATP-WR and MIBG-WR and HbA1c were found (r = -0.52 [P = 0.02] and −0.47 [P = 0.03], respectively). Although no correlation was found between ATP-WR values and the early phase H/M ratio, a significant positive correlation was observed between ATP-WR and H/M ratio (r = 0.54; P = 0.02).
In the present study in Japanese diabetic patients without subjective signs of coronary artery disease and without abnormalities on ECG or echocardiography, ATP-WR, an indicator of myocardial blood flow, was correlated with myocardial sympathetic nerve dysfunction and 24-month glycemic control. However, sympathetic nerve dysfunction was not correlated with 24-month glycemic control.
PMCID: PMC3966002  PMID: 24678078
cardiac sympathetic nervous dysfunction; ATP T1-201 myocardial scintigraphy; I-123 metaiodobenzylguanidine scintigraphy; glycemic control
7.  Increased myocardial [123I]-metaiodobenzylguanidine uptake after enalapril treatment in patients with chronic heart failure. 
Heart  1996;76(3):218-222.
OBJECTIVE: To assess non-invasively the effect of enalapril on cardiac sympathetic neuronal uptake function in patients with congestive heart failure, by using [123I]-metaiodobenzylguanidine (MIBG), which is a noradrenaline analogue. Cardiac MIBG uptake was visualised by single photon emission tomography (SPET). In addition, plasma noradrenaline concentration, indicating systemic sympathetic activity, was measured to see whether it was related to cardiac MIBG uptake. DESIGN: Consecutive patients were treated with enalapril and served as their own controls. SETTING: Cardiac unit of a tertiary care centre. PATIENTS: 23 Patients with chronic, mild to moderate, stable congestive heart failure, and a left ventricular ejection fraction less than 40%. Heart failure was caused by ischaemic heart disease or was idiopathic. INTERVENTIONS: Cardiac MIBG SPET was performed and plasma noradrenaline concentration was measured before and after 6 weeks treatment with enalapril. MAIN OUTCOME MEASURES: Cardiac uptake of MIBG was measured by using the left ventricular cavity and a venous blood sample as a reference. RESULTS: Cardiac uptake of MIBG increased significantly after enalapril treatment, indicating improved cardiac neuronal uptake function. Plasma noradrenaline concentration did not decrease significantly. Cardiac MIBG uptake was not related to plasma noradrenaline concentration. CONCLUSIONS: Cardiac MIBG SPET can be used to assess changes in cardiac sympathetic neuronal uptake function caused by pharmacological intervention. Enalapril seemed to improve cardiac sympathetic neuronal uptake function but did not significantly affect plasma noradrenaline concentrations in a group of patients with predominantly moderate heart failure. These results accord with the hypothesis that restoration of cardiac neuronal uptake of noradrenaline is one of the beneficial effects of enalapril in such patients.
PMCID: PMC484510  PMID: 8868979
8.  Cardiac Autonomic Nervous System in Heart Failure: Imaging Technique and Clinical Implications 
Current Cardiology Reviews  2011;7(1):35-42.
The autonomic nervous system interacts in the pathophysiology of heart failure. Dysfunction of the sympathetic nervous system has been identified as an important prognostic marker in patients with chronic heart failure. At present, cardiac sympathetic nerve imaging with 123-iodine metaiodobenzylguanidine [123-I MIBG] has been employed most frequently for the assessment of cardiac sympathetic innervation and activation pattern. The majority of studies have shown that cardiac sympathetic dysfunction as assessed with 123-I MIBG imaging is a powerful predictor for heart failure mortality and morbidity. Additionally, 123-I MIBG imaging can be used for prediction of potentially lethal ventricular tachyarrhythmias in heart failure patients. At present however, the lack of standardization of 123-I MIBG imaging procedures represents an evident issue. Standardized criteria on the use of 123-I MIBG imaging will further strengthen the clinical use of 123-I MIBG imaging in heart failure patients.
PMCID: PMC3131714  PMID: 22294973
Cardiac 123-iodine metaiodobenzylguanidine imaging; heart failure; heart-to-mediastinum ratio; myocardial sympathetic innervation; prognosis; ventricular arrhythmia.
9.  123I-MIBG Scintigraphy as a Powerful Tool to Plan an Implantable Cardioverter Defibrillator and to Assess Cardiac Resynchronization Therapy in Heart Failure Patients 
Iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy is a nuclear medicine technique which describes the functional status of the cardiac sympathetic nervous system. It is well known that an autonomic dysfunction is present in heart failure setting as a neuronal uptake of norepinephrine is impaired in the failing myocardium. Reduction in sympathetic nervous function in the heart, measured by reduced myocardial uptake of 123I-MIBG, is an indicator of poor prognosis for heart failure patients. The aim of this paper was to investigate the role of 123I-MIBG scintigraphy in evaluating the need of implantable cardioverter defibrillator (ICD) and the response to cardiac resynchronization therapy (CRT) in heart failure patients. For this purpose scientific literature data on these topics were reviewed. Based on literature data, 123I-MIBG scintigraphy seems to be a useful tool to assess which patients may benefit most from an ICD implantation to reduce the risk of ventricular arrhythmia or sudden cardiac death. Furthermore, 123I-MIBG scintigraphy seems to predict which patients will response to CRT with an improvement in left ventricular function.
PMCID: PMC3463902  PMID: 23056938
10.  The role of nuclear imaging in the failing heart: myocardial blood flow, sympathetic innervation, and future applications 
Heart Failure Reviews  2010;16(4):411-423.
Heart failure represents a common disease affecting approximately 5 million patients in the United States. Several conditions play an important role in the development and progression of heart failure, including abnormalities in myocardial blood flow and sympathetic innervation. Nuclear imaging represents the only imaging modality with sufficient sensitivity to assess myocardial blood flow and sympathetic innervation of the failing heart. Although nuclear imaging with single-photon emission computed tomography (SPECT) is most commonly used for the evaluation of myocardial perfusion, positron emission tomography (PET) allows absolute quantification of myocardial blood flow beyond the assessment of relative myocardial perfusion. Both techniques can be used for evaluation of diagnosis, treatment options, and prognosis in heart failure patients. Besides myocardial blood flow, cardiac sympathetic innervation represents another important parameter in patients with heart failure. Currently, sympathetic nerve imaging with 123-iodine metaiodobenzylguanidine (123-I MIBG) is often used for the assessment of cardiac innervation. A large number of studies have shown that an abnormal myocardial sympathetic innervation, as assessed with 123-I MIBG imaging, is associated with increased mortality and morbidity rates in patients with heart failure. Also, cardiac 123-I MIBG imaging can be used to risk stratify patients for ventricular arrhythmias or sudden cardiac death. Furthermore, novel nuclear imaging techniques are being developed that may provide more detailed information for the detection of heart failure in an early phase as well as for monitoring the effects of new therapeutic interventions in patients with heart failure.
PMCID: PMC3118005  PMID: 20938735
Nuclear imaging; Myocardial blood flow; Sympathetic innervation; Heart failure
11.  Radiolabeled Phenethylguanidines 
Journal of medicinal chemistry  2007;50(9):2078-2088.
The norepinephrine transporter (NET) substrates [123I]meta-iodobenzylguanidine (MIBG) and [11C]meta-hydroxyephedrine (HED) are used as markers of cardiac sympathetic neurons and adrenergic tumors (pheochromocytoma, neuroblastoma). However, their rapid NET transport rates limit their ability to provide accurate measurements of cardiac nerve density. [11C]Phenethylguanidine ([11C]1a) and 12 analogs ([11C]1b-m) were synthesized and evaluated as radiotracers with improved kinetics for quantifying cardiac nerve density. In isolated rat hearts, neuronal uptake rates of [11C]1a-m ranged from 0.24 to 1.96 mL/min/g wet, and six compounds had extremely long neuronal retention times (clearance T1/2 > 20 hr) due to efficient vesicular storage. PET studies in nonhuman primates with [11C]1e, N-[11C]guanyl-meta-octopamine, which has a slow NET transport rate, showed improved myocardial kinetics compared to HED. Compound [11C]1c, [11C]para-hydroxyphenethylguandine, which has a rapid NET transport rate, avidly accumulated into rat pheochromocytoma xenograft tumors in mice. These encouraging findings demonstrate that radiolabeled phenethylguanidines deserve further investigation as radiotracers of cardiac sympathetic innervation and adrenergic tumors.
PMCID: PMC2625310  PMID: 17419605
12.  Dependence of Cardiac 11C-meta-Hydroxyephedrine Retention on Norepinephrine Transporter Density 
The norepinephrine analog 11C-meta-hydroxyephedrine (HED) is used with PET to map the regional distribution of cardiac sympathetic neurons. HED is rapidly transported into sympathetic neurons by the norepinephrine transporter (NET) and stored in vesicles. Although much is known about the neuronal mechanisms of HED uptake and retention, there is little information about the functional relationship between HED retention and cardiac sympathetic nerve density. The goal of this study was to characterize the dependence of HED retention on nerve density in rats with graded levels of cardiac denervation induced chemically with the neurotoxin 6-hydroxydopamine (6-OHDA).
Thirty male Sprague–Dawley rats were divided into 6 groups, and each group was administered a different dose of 6-OHDA: 0 (controls), 7, 11, 15, 22, and 100 mg/kg intraperitoneally. One day after 6-OHDA injection, HED (3.7–8.3 MBq) was injected intravenously into each animal and HED concentrations in heart and blood at 30 min after injection were determined. Heart tissues were frozen and later processed by tissue homogenization and differential centrifugation into a membrane preparation for in vitro measurement of cardiac NET density. A saturation binding assay using 3H-mazindol as the radioligand was used to measure NET density (maximum number of binding sites [Bmax], fmol/mg protein) for each heart.
In control animals, NET Bmax was 388 ± 23 fmol/mg protein and HED heart uptake (HU) at 30 min was 2.89% ± 0.35 %ID/g (%ID/g is percentage injected dose per gram tissue). The highest 6-OHDA dose of 100 mg/kg caused severe cardiac denervation, decreasing both NET Bmax and HED HU to 8% of their control values. Comparing values for all doses of 6-OHDA, HED retention had a strong linear correlation with NET density: HU = 0.0077Bmax − 0.028, r2 = 0.95.
HED retention is linearly dependent on NET density in rat hearts that have been chemically denervated with 6-OHDA, suggesting that HED retention is a good surrogate measure of NET density in the rat heart. This finding is discussed in relation to clinical observations of the dependence of HED retention on cardiac nerve density in human subjects using PET.
PMCID: PMC1618973  PMID: 16954558
sympathetic nervous system; meta-hydroxyephedrine; 6-hydroxydopamine; norepinephrine transporter; PET
13.  Altered atrial neurotransmitter release in transgenic p75 −/− and gp130 KO mice 
Neuroscience letters  2012;529(1):55-59.
Heart rate is controlled by stimulatory sympathetic and inhibitory parasympathetic nerves innervating the sino-atrial node and cardiac conduction system. Sympathetic release of norepinephrine (NE) and parasympathetic release of acetylcholine (ACh) are controlled by the central nervous system, and by pre-synaptic inhibition of transmitter release within the atria. An increase in cardiac sympathetic transmission relative to parasympathetic transmission is pathological as it can lead to disturbances in heart rhythm, catecholaminergic toxicity and development of arrhythmias or fibrillation. Mice lacking the p75 neurotrophin receptor (p75−/−) have elevated atrial NE but a low heart rate suggesting autonomic dysregulation. Similarly, mice whose sympathetic neurons lack the gp130 cytokine receptor (gp130 KO) have a normal heart rate but enhanced bradycardia after vagal nerve stimulation. What is unclear is whether cardiac autonomic disturbances in these animals reflect systemic alterations in nerve activity or whether localized defects in neurotransmitter stores or release are involved. To examine local stimulus-evoked release of neurotransmitters, we have developed a novel method for simultaneous quantification of both NE and ACh after ex-vivo atrial field stimulation. Using HPLC with electrochemical detection for NE, and HPLC with mass spectrometry for ACh, we found that following field stimulation NE release was impaired in p75−/− atria while ACh content and release was elevated in gp130 KO atria. Thus, alterations in localized transmitter release from atrial explants are consistent with in vivo deficits in heart rate control, suggesting peripheral alterations in autonomic transmission in these mice.
PMCID: PMC3478480  PMID: 22999927
Heart; autonomic; HPLC-MS; HPLC-ED; sympathetic; parasympathetic
14.  Clonidine, an α2 receptor agonist, diminishes GABAergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus 
Brain research  2010;1347:65-70.
In hypertension there is an autonomic imbalance in which sympathetic activity dominates over parasympathetic control. Parasympathetic activity to the heart originates from cardiac vagal neurons located in the nucleus ambiguus. Pre-sympathetic neurons that project to sympathetic neurons in the spinal cord are located in the ventral brainstem in close proximity to cardiac vagal neurons, and many of these pre-sympathetic neurons are catecholaminergic. In addition to their projection to the spinal cord, many of these pre-sympathetic neurons have axon collaterals that arborize into neighboring cardio-respiratory locations and likely release norepinephrine onto nearby neurons. Activation of α2 adrenergic receptors in the central nervous system evokes a diverse range of physiological effects, including reducing blood pressure. This study tests whether clonidine, an α2 adrenergic receptor agonist, alters excitatory glutamatergic, and/or inhibitory GABAergic or glycinergic synaptic neurotransmission to cardiac vagal neurons in the nucleus ambiguus. Cardiac vagal neurons were identified in a in-vitro brainstem slice preparation and synaptic events were recording using whole cell voltage clamp methodologies. Clonidine significantly inhibited GABAergic neurotransmission, but had no effect on glycinergic or glutamatergic pathways to cardiac vagal neurons. This diminished inhibitory GABAergic neurotransmission to cardiac vagal neurons would increase parasympathetic activity to the heart, decreasing heart rate and blood pressure. The results presented here provide a cellular substrate for the clinical use of clonidine as a treatment for hypertension as well as a role in alleviating post-traumatic stress disorder by evoking an increase in parasympathetic cardiac vagal activity, and a decrease in heart rate and blood pressure.
PMCID: PMC2909326  PMID: 20553874
ambiguus; clonidine; adrenergic; cardiac; vagal; parasympathetic
15.  Developmental Neurotoxicity Targeting Hepatic and Cardiac Sympathetic Innervation: Effects of Organophosphates are Distinct from those of Glucocorticoids 
Brain research bulletin  2011;85(3-4):225-230.
Early-life exposure to organophosphate pesticides leads to subsequent hyperresponsiveness of β-adrenergic receptor-mediated cell signaling that regulates hepatic gluconeogenesis, culminating in metabolic abnormalities resembling prediabetes. In the current study, we evaluated the effects of chlorpyrifos or parathion on presynaptic sympathetic innervation to determine whether the postsynaptic signaling effects are accompanied by defects in neuronal input. We administered either chlorpyrifos or parathion to newborn rats using exposure paradigms known to elicit the later metabolic changes but found no alterations in either hepatic or cardiac norepinephrine levels in adolescence or adulthood. However, shifting chlorpyrifos exposure to the prenatal period did evoke changes: exposure early in gestation produced subsequent elevations in norepinephrine, whereas later gestational exposure produced significant deficits. We also distinguished the organophosphate effects from those of the glucocorticoid, dexamethasone, a known endocrine disruptor that leads to later-life metabolic and cardiovascular disruption. Postnatal exposure to dexamethasone elicited deficits in peripheral norepinephrine levels but prenatal exposure did not. Our results indicate that early-life exposure to organophosphates leads to subsequent abnormalities of peripheral sympathetic innervation through mechanisms entirely distinct from those of glucocorticoids, ruling out the possibility that the organophosphate effects are secondary to stress or disruption of the HPA axis. Further, the effects on innervation were separable from those on postsynaptic signaling, differing in critical period as well as tissue- and sex-selectivity. Organophosphate targeting of both presynaptic and postsynaptic β-adrenergic sites, each with different critical periods of vulnerability, thus sets the stage for compounding of hepatic and cardiac functional abnormalities.
PMCID: PMC3109170  PMID: 21453761
β-Adrenergic receptor; Dexamethasone; Glucocorticoids; Heart; Liver; Norepinephrine; Organophosphate insecticides; Parathion; Sympathetic nervous system
16.  Regulation of cardiac innervation and function via the p75 neurotrophin receptor 
Homeostatic regulation of cardiac function is dependent on the balance of inputs from the sympathetic and parasympathetic nervous systems. We investigated whether the p75 neurotrophin receptor plays a developmental role in cardiac innervation by analyzing sympathetic and parasympathetic fibers in the atria of p75 knockout and wildtype mice at several stages of postnatal development, and examining the effect on control of heart rate. We found that parasympathetic innervation of the atria in p75-/-mice was similar to wildtype at all time points, but that the density of sympathetic innervation was dynamically regulated. Compared to wildtype mice, the p75-/- mice had less innervation at postnatal day 4, an increase at day 28, and decreased innervation in adult mice. These changes reflect defects in initial fiber ingrowth and the timing of the normal developmental decrease in sympathetic innervation density in the atria. Thus, p75 regulates both the growth and stability of cardiac sympathetic fibers. The distribution of sympathetic fibers was also altered, so that many regions lacked innervation. Basal heart rate was depressed in adult p75-/- mice, and these mice exhibited a diminished heart rate response to restraint stress. This resulted from the lack of sympathetic innervation rather than increased parasympathetic transmission or a direct effect of p75 in cardiac cells. Norepinephrine was elevated in p75-/- atria, but stimulating norepinephrine release with tyramine produced less tachycardia in p75-/- mice than wild type mice. This suggests that altered density and distribution of sympathetic fibers in p75-/- atria impairs the control of heart rate.
PMCID: PMC2475591  PMID: 18430612
axon outgrowth; axon maintenance; sympathetic; parasympathetic; development; autonomic control
17.  11C-meta-hydroxyephedrine defects persist despite functional improvement in hibernating myocardium 
Regional cardiac sympathetic nerve dysfunction develops in hibernating myocardium and may play a role in its association with sudden cardiac death. Interventions to improve cardiac function (i.e., revascularization) improve survival, but the potential reversibility of sympathetic nerve dysfunction remains unclear.
Methods and Results
Pigs (n = 11) were chronically instrumented with a proximal left anterior descending coronary artery (LAD) stenosis to produce hibernating myocardium. Prior to therapeutic interventions, there was LAD occlusion with collateral-dependent myocardium, reduced regional function (echocardiographic LAD wall-thickening 23% ± 4% vs 83% ± 6% in Remote, P < .001), and large defects in 11C-meta-hydroxyephedrine (HED) PET (48% ± 4% of LV area, 26% ± 2% integrated reduction). Successful PCI or pravastatin therapy improved regional (LAD wall-thickening 23% ± 4% to 42% ± 6%, P < .05) and global LV function (fractional shortening 24% ± 2% to 31% ± 2%, P < .01), but did not alter regional HED uptake, retention, defect size, or defect severity.
Despite significant functional improvement of hibernating myocardium as a result of PCI or pravastatin therapy, there were no changes in HED defect size or severity. Thus, inhomogeneity in myocardial sympathetic innervation persisted, and the lack of plasticity suggests that even in the absence of significant infarction, structural rather than functional defects are responsible for reduced myocardial norepinephrine uptake in chronic ischemic heart disease. (J Nucl Cardiol 2009)
PMCID: PMC2825874  PMID: 19902319
Hibernating myocardium; isotopes; sympathetic nervous system
18.  Baroreflex control of plasma norepinephrine and heart period in healthy subjects and diabetic patients. 
Journal of Clinical Investigation  1986;78(2):366-374.
Resting diabetic patients may have excessively rapid heart rates, reduced heart rate variability, and subnormal plasma catecholamine levels. Although all of these abnormalities may relate in some way to baroreceptor reflex function, there have been surprisingly few attempts to evaluate systematically baroreflex mechanisms in diabetic patients. Accordingly, we studied autonomic responses over a range of pharmacologically induced arterial pressure changes in 10 unselected young adult insulin-dependent diabetic patients who had no symptoms of autonomic neuropathy, and 12 age-matched nondiabetic subjects. Sympathetic responses were estimated from antecubital vein plasma norepinephrine levels, and parasympathetic responses were estimated from electrocardiographic R-R intervals and their variability (standard deviation). Both were correlated with other noninvasive indexes of peripheral and central nervous system function. Multiple derangements of baroreflex function were found in the diabetic patients studied. Sympathetic abnormalities included subnormal baseline norepinephrine levels, virtual absence of changes of norepinephrine levels during changes of arterial pressure, and supranormal pressor responses to phenylephrine infusions. Parasympathetic abnormalities included subnormal baseline standard deviations of R-R intervals, and R-R interval prolongations during elevations of arterial pressure which were unmistakably present, but subnormal. Our data suggest that in diabetic patients, subnormal baseline plasma norepinephrine levels may signify profound, possibly structural defects of sympathetic pathways. Subnormal resting levels of respiratory sinus arrhythmia may have different implications, however, since vagal, unlike sympathetic reflex abnormalities, can be reversed partly by arterial pressure elevations.
PMCID: PMC423555  PMID: 3734097
19.  Effects of cardiac sympathetic innervation on regional wall motion abnormality in patients with long QT syndrome 
Heart  2000;83(3):295-300.
AIM—To assess the spatial relation between regional cardiac sympathetic innervation and regional ventricular repolarisation indicated by ventricular wall motion abnormality in patients with congenital long QT syndrome.
DESIGN—Regional percentage uptake and washout rate of 123I metaiodobenzylguanidine (MIBG) were measured to assess cardiac sympathetic innervation in septum, anterior wall, lateral wall, and posterior wall. Left ventricular short axis images on echocardiography were digitised to reconstruct digitised M mode echocardiograms, from which left ventricular wall thickness curves were obtained. The wall thickening time (ThT) was defined as the period in which the instantaneous wall thickness exceeded 90% of the maximum wall thickness. The ThT was measured from the ventricular wall thickness curve at the same segments where regional percentage uptake and washout rate of 123I MIBG were measured.
PATIENTS—Seven patients with long QT syndrome.
RESULTS—The regional washout rate (mean (SD)) of 123I MIBG in patients with long QT syndrome was greater in the segments with decreased percentage uptake of 123I MIBG than in those without (17.4 (10.6)% v 9.7 (16.5)%, p < 0.03). ThT in segments both with and without decreased percentage uptake of 123I MIBG was longer than in control subjects (p < 0.0001). ThT was longer in the segments with decreased percentage uptake of 123I MIBG than in those without (199 (70) ms v 150 (66) ms, p = 0.0018).
CONCLUSIONS—Activation of regional cardiac sympathetic terminals is likely to participate in additional regional prolongation of ventricular repolarisation in patients with long QT syndrome.

Keywords: long QT syndrome; sympathetic innervation; regional wall motion
PMCID: PMC1729335  PMID: 10677409
20.  Altered norepinephrine content and ventricular function in p75NTR−/− mice after myocardial infarction 
Cardiac sympathetic neurons stimulate heart rate and the force of contraction through release of norepinephrine. Nerve growth factor modulates sympathetic transmission through activation of TrkA and p75NTR. Nerve growth factor plays an important role in post-infarct sympathetic remodeling. We used mice lacking p75NTR to examine the effect of altered nerve growth factor signaling on sympathetic neuropeptide expression, cardiac norepinephrine, and ventricular function after myocardial infarction. Infarct size was similar in wildtype and p75NTR−/− mice after ischemia-reperfusion surgery. Likewise, mRNAs encoding vasoactive intestinal peptide, galanin, and pituitary adenylate cyclase activating peptides were identical in wildtype and p75NTR−/− cardiac sympathetic neurons, as was expression of the TrkA neurotrophin receptor. Norepinephrine content was elevated in the base of the p75NTR−/− ventricle compared to wildtype, but levels were identical below the site of occlusion. Left ventricular pressure, dP/dtMAX, and dP/dtMIN were measured under isoflurane anesthesia 3 and 7 days after surgery. Ventricular pressure decreased significantly 3 days after infarction, and deficits in dP/dtMAX were revealed by stimulating beta receptors with dobutamine and release of endogenous norepinephrine with tyramine. dP/dtMIN was not altered by genotype or surgical group. Few differences were observed between genotypes 3 days after surgery, in contrast to low pressure and dP/dtMAX previously reported in control p75NTR−/− animals. Seven days after surgery ventricular pressure and dP/dtMAX were significantly lower in p75NTR−/− hearts compared to WT hearts. Thus, the lack of p75NTR did not enhance cardiac function after myocardial infarction.
PMCID: PMC3167025  PMID: 21646052
cardiac ischemia-reperfusion; norepinephrine; nerve growth factor
21.  Pulmonary vein isolation in patients with paroxysmal atrial fibrillation is associated with regional cardiac sympathetic denervation 
EJNMMI Research  2013;3:81.
Circumferential pulmonary vein isolation (PVI) is the cornerstone of the current state-of-the-art management of atrial fibrillation (AF). However, the precise mechanisms behind AF relapses post PVI are still unknown. Since the activity of the autonomous nervous system is crucial in triggering paroxysmal AF, we hypothesized that PVI is associated with changes of cardiac sympathetic activity.
Sixteen patients with paroxysmal AF underwent cardiac iodine-123-meta-iodobenzylguanidine (123I-mIBG) planar cardiac imaging and single-photon emission computed tomography with low-dose computed tomography (SPECT/CT) for attenuation correction before and 4 weeks after PVI. The heart-to-mediastinum ratio (H/M ratio), washout rate (WR), regional myocardial uptake, and regional washout were analyzed.
The late H/M ratio was unchanged by PVI (pre, 2.9 ± 0.5 vs. post, 2.7 ± 0.6, p = 0.53). Four of the 16 patients (25%) displayed regional deficits before PVI. After PVI, regional deficits were present in ten patients (62.5%) with newly emerging deficits localized in the inferolateral wall. In a 6-month follow-up, four out of the ten patients (40%) with regional 123I-mIBG defects suffered from a recurrence of AF, while only one of the six patients (16.7%) without a regional 123I-mIBG defect experienced a recurrence.
A significant number of patients with paroxysmal AF show regional cardiac sympathetic innervation deficits at baseline. In addition, PVI is associated with newly emerging defects. The presence of regional sympathetic denervation after PVI may correlate with the risk of AF relapses.
PMCID: PMC3892075  PMID: 24360192
Atrial fibrillation; Pulmonary vein isolation; Sympathetic nervous system; Imaging; Single-photon emission computed tomography
22.  A clinical role for [123I]MIBG myocardial scintigraphy in the distinction between dementia of the Alzheimer's-type and dementia with Lewy bodies 
OBJECTIVE—Scintigraphy with [123I]metaiodobenzyl guanidine ([123I]MIBG) enables the quantification of postganglionic sympathetic cardiac innervation. Recently, myocardial [123I]MIBG scintigraphy has been found to be useful in distinguishing Parkinson's disease, a Lewy body disease, from other akinetic rigid syndromes. Some patients initially diagnosed with dementia of the Alzheimer's type (DAT) are discovered to have an alternative disease such as dementia with Lewy bodies (DLB), despite the application of stringent diagnostic criteria. In the present study, examinations were performed to clarify the usefulness of myocardial [123I]MIBG scintigraphy in improving the differential diagnosis between patients with DLB and DAT.
METHODS—Fourteen patients with DLB and 14 patients with DAT underwent scintigraphy with [123I]MIBG, combined with orthostatic tests and cardiac examinations.
RESULTS—In all patients with DLB, the heart to mediastinum (H/M) ratio of MIBG uptake was pathologically impaired in both early and delayed images, independently of the duration of disease and autonomic failure. All patients with DAT had successful MIBG uptake in the heart regardless of duration of disease and autonomic failure. Orthostatic hypotension was seen in four patients with DAT and 13 patients with DLB.
CONCLUSIONS—[123I]MIBG myocardial scintigraphy might detect early disturbances of the sympathetic nervous system in DLB and might provide useful diagnostic information to discriminate DLB from DAT. The distinction between DLB and DAT may be improved by greater emphasis on cardiac sympathetic disturbances.

PMCID: PMC1737586  PMID: 11606666
23.  Autonomic pathophysiology in heart failure patients. Sympathetic-cholinergic interrelations. 
Journal of Clinical Investigation  1990;85(5):1362-1371.
We conducted this study in an effort to characterize and understand vagal abnormalities in heart failure patients whose sympathetic activity is known. We measured sympathetic (peroneal nerve muscle sympathetic recordings and antecubital vein plasma norepinephrine levels) and vagal (R-R intervals and their standard deviations) activities in eight heart failure patients and eight age-matched healthy volunteers, before and after parasympathomimetic and parasympatholytic intravenous doses of atropine sulfate. At rest, sympathetic and parasympathetic outflows were related reciprocally: heart failure patients had high sympathetic and low parasympathetic outflows, and healthy subjects had low sympathetic and high parasympathetic outflows. Low dose atropine, which is known to increase the activity of central vagal-cardiac motoneurons, significantly increased R-R intervals in healthy subjects, but did not alter R-R intervals in heart failure patients. Thus, our data document reciprocal supranormal sympathetic and subnormal parasympathetic outflows in heart failure patients and suggest that these abnormalities result in part from abnormalities within the central nervous system.
PMCID: PMC296581  PMID: 2332495
24.  Prognostic value of iodine-123 metaiodobenzylguanidine imaging in patients with heart failure 
Abnormalities of myocardial sympathetic nerve function were reported in congestive heart failure (CHF). To assess myocardial sympathetic nerve function, we obtained metaiodobenzylguanidine (MIBG) images 15 min and 180 min after the injection of iodine-123 MIBG at a dose of 111 MBq and calculated the ratio of heart to mediastinum count (H/M) and the washout rates (WRs) in 59 consecutive patients with CHF and age-matched subjects without CHF (n=23). The plasma levels of B-type natriuretic peptide were measured. H/M ratio was significantly lower in the CHF group (1.8±0.9) than in the control group (2.6±0.4; P<0.01). WR was higher in the CHF group (38±4%) than in the control group (28±3%; P<0.01). H/M was inversely correlated with the plasma B-type natriuretic peptide (r=−0.46, P<0.05). Eighteen patients suffered cardiac events (two deaths, 16 hospitalizations) during a mean follow-up period of three years. Kaplan-Meier analysis showed that a low H/M was associated with a poor prognosis in patients with CHF. These findings indicate that the H/M ratio on MIBG imaging is a useful predictor of mortality and morbidity in patients with CHF.
PMCID: PMC2716206  PMID: 19641657
B-type natriuretic peptide; Congestive heart failure; Heart-to-mediastinum count ratio; Metaiodobenzylguanidine; Washout rates
25.  Impaired cardiac adrenergic innervation assessed by MIBG imaging as a predictor of treatment response in childhood dilated cardiomyopathy 
Heart  2001;85(6):692-696.
OBJECTIVE—To evaluate the prognostic value of metaiodobenzylguanidine (MIBG) imaging in childhood cardiomyopathy.
DESIGN—Prospective cohort study.
SETTING—Tertiary referral centre.
PATIENTS—40 children (21 boys, 19 girls; mean (SD) age, 7.0 (5.6) years) with heart failure resulting from idiopathic dilated cardiomyopathy (n = 23) or various other disorders (n = 17).
METHODS—At the initial examination, cardiac 123I-MIBG uptake and release, circulating noradrenaline (norepinephrine) concentration, x ray cardiothoracic ratio, and echocardiographic variables were recorded. Cardiac MIBG uptake was obtained by measuring the heart to mediastinum activity ratio on the planar image obtained four hours after MIBG injection. MIBG washout rate was evaluated using relative decrease in cardiac activity measured at 20 minutes and four hours. Patients were treated with angiotensin converting enzyme inhibitors, diuretics, and digitalis, and were followed up for 12 (10) months. Fifteen patients did not respond to medical treatment (12 heart transplants; three deaths), and 25 did respond (improved or stable).
RESULTS—Cardiac MIBG uptake was positively correlated with x ray cardiothoracic index (r = 0.55, p = 0.0008) and echocardiographic left ventricular fractional shortening (r = 0.68, p < 0.0001). Among all the clinical and laboratory variables tested, multivariate discriminant analysis showed that the only independent predictor of an unfavourable outcome was a low MIBG uptake (p < 0.001). Survival curves had a mean threshold value of 1.54 for MIBG uptake.
CONCLUSIONS—Impaired cardiac adrenergic innervation is strongly related to adverse outcome in children with dilated cardiomyopathy, independently of the aetiology. MIBG imaging may help to stratify risk in such patients.

Keywords: noradrenaline; MIBG; single photon imaging; children; cardiomyopathy
PMCID: PMC1729756  PMID: 11359754

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