performed and resulted in a required number of 44 in- cluded patients. Initially, patients with CAD detected on pre-HD myocardial perfusion SPECT were excluded from this study. Due to a very slow inclusion of patients with no CAD at all, we decided to also include patients with CAD in pre-HD. This did not result in an increase in the inclusion rate. Therefore, the study was terminated before the necessary number of patients was included. Eventually, only 18 patients completed the study protocol. If the required number of patients had been included, the results might have been more definitive. However, the present study comprises the largest group of patients in which cardiac sympathetic innervation has been evaluated during the initiation of maintenance HD.
Although BDNF expression is much higher in gWAT of adult female mice (e.g., 6 weeks old), BDNF expres- sion levels did not exhibit any sex differences in develop- ing adipose tissue. Importantly, BDNF expression was upregulated by estrogen treatment in vitro, and VCD- induced ovarian failure reduced BDNF expression. These data indicated that BDNF is an estrogen-sensitive neuro- trophic factor that contributes to differential sympathetic innervation of gWAT. Although the mechanism of BDNF induction by estrogen is not determined in this study, the promoter of the BDNF gene contains estrogen response elements (ERE) [30–32]. VCD, a well- established ovarian toxicant, has been used to induce ovarian failure . However, we do not exclude un- known off-target effects of VCD treatment. Thus, fur- ther confirmation with surgical ovariectomy models in combination with estrogen replacement would be in- formative to support ovarian steroid hormone-specific effects on browning of gWAT. As mentioned above, in- nervation levels in iWAT did not differ between male and female mice, suggesting that distinct mechanisms
13 Read more
Background: Graphical methods of radiotracer kinetic modeling in PET are ideal for parametric imaging and data quality assurance but can suffer from noise bias. This study compared the Logan and Multilinear Analysis-1 (MA1) graphical models to the standard one-tissue-compartment (1TC) model, including correction for partial-volume effects, in dynamic PET-CT studies of myocardial sympathetic innervation in the left ventricle (LV) using [ 11 C]HED. Methods: Test and retest [ 11 C]HED PET imaging (47 ± 22 days apart) was performed in 18 subjects with heart failure symptoms. Myocardial tissue volume of distribution (V T ) was estimated using Logan and MA1 graphical
11 Read more
In TTC patients, 123 I-mIBG scintigraphy revealed al- tered cardiac sympathetic innervation, with absent or strongly reduced tracer uptake at the hypocontractile zones (mean LV defect, 38 ± 17%) [23,30]. The topography and extent of glucose metabolism defects ( 18 F-FDG) and sympathetic innervation abnormalities ( 123 I-mIBG) were largely overlapping . At 12 months and despite pro- gressive evolution, all controlled patients presented with incomplete recovery of apical 123 I-mIBG uptake . Fi- nally, the initial impairment of cardiac sympathetic in- nervation after SAH (90% of patients, mean defect 28 ± 18%) differed from that of TTC (100% of patients, mean defect 38 ± 17%) regarding its heterogeneous and non-systematized distribution.
11 Read more
contribute to the sympathetic innervation of the heart revealed neu- ronal loss due to excess apoptosis at the late embryonic stage, but not due to failure in neuronal migration, differentiation, or proliferation. These findings are consistent with previous reports that increased pyknosis is detected from E16.5 in NGF-targeted mice and that NGF transported from target organs acts on survival of innervating neurons, but not on proliferation or differentiation of sympathetic neurons (24). Developing axons are guided to their targets and maintained by extra- cellular molecules. Neurotrophin-3 is also a critical factor for the sur- vival and differentiation of sympathetic neurons (2, 5, 28). However, neurotrophin-3 was not downregulated in Edn1 –/– heart, and the sym-
10 Read more
Results: Here report that growth differentiation factor 5 (GDF5), a widely expressed member of the transforming growth factor beta (TGF β ) superfamily required for limb development, promoted axon growth from mouse superior cervical ganglion (SCG) neurons independently of NGF and enhanced axon growth in combination with NGF. GDF5 had no effect on neuronal survival and influenced axon growth during a narrow window of postnatal development when sympathetic axons are ramifying extensively in their targets in vivo. SCG neurons expressed all receptors capable of participating in GDF5 signaling at this stage of development. Using compartment cultures, we demonstrated that GDF5 exerted its growth promoting effect by acting directly on axons and by initiating retrograde canonical Smad signalling to the nucleus. GDF5 is synthesized in sympathetic targets, and examination of several anatomically circumscribed tissues in Gdf5 null mice revealed regional deficits in sympathetic innervation. There was a marked, highly significant reduction in the sympathetic innervation density of the iris, a smaller though significant reduction in the trachea, but no reduction in the submandibular salivary gland. There was no reduction in the number of neurons in the SCG.
13 Read more
The purpose of this investigation was to study the characteristics of arterial wall and sympathetic innervation of the human posterior intercostal artery (PIA) in or- der to assess its suitability as an arterial graft for vascular surgeries. Fifty PIA sam- ples were obtained from 25 cadavers (18 males and 7 females). Samples were divided into three age groups: group 1: 19–40 years; group 2: 41–60 years; and group 3 over 61 years. Sections (5 µm-thickness) of each sample were taken and stained with haematoxylin-eosin, Verhoeff’s-Van Gieson. Five samples were pro- cessed for tyrosine hydroxylase immunostaining. The differences in the thickness of tunica intima were not statistically significant when group 1 was compared with group 2 (p = 0.798), but significant differences were observed in the thickness of the tunica intima when comparing group 2 with group 3 (p = 0.012) and group 3 with group 1 (p = 0.002). The tunica media was not statistically significant when group 1 was compared with group 2 (p = 0.479). However, significant differences were observed in the thickness of the tunica media when comparing group 2 with group 3 (p = 0.001) and group 3 with group 1 (p = 0.011). The mean (SD) number of elastic laminae in group 1, group 2, and group 3 were 7.88 ± 0.69, 6.62 ± 0.51, and 4.56 ± 0.82, respectively. Tunica intima/media ratios in groups 1, 2, and 3 were found to be 0.09 ± 0.01, 0.11 ± 0.02, and 0.27 ± 0.16, respec- tively. Tyrosine hydroxylase immunostaining revealed that sympathetic fibres are found mainly in the tunica adventitia and at the adventitia-medial border. The sympathetic nerve fibre area and sympathetic index were found to be 0.004 mm 2 ,
Impaired cardiac adrenergic innervation as assessed by I-123 mIBG imaging is strongly related to mortality in patients with HF independently of its cause from prior studies . Use of I-123 mIBG is now an FDA approved indication for use in NYHA class 2 - 3 SHF patients with EF of 30% - 35% when additional risk stratification is desired prior to ICD placement. Patients with SHF have a higher likelihood of LVMD which is linked to sudden cardiac death. CRT is approved for the treatment of patients with NYHA class III/IV heart failure symptoms who have ejection fractions of 35% or less and a QRS duration of greater than 120 milliseconds on a surface electrocardiogram. Several studies have shown benefits with CRT when added to optimal medical therapy for groups of patients who meet these selection criteria. These benefits include improved functional status, exercise tolerance, quality of life, and left ventricular reverse remodeling -. Prior studies have evaluated the rela- tionship between LVMD and cardiac sympathetic innervation. In one study looking at relationship between MRI derived dyssynchrony parameters (spatial and temporal) and H/M ratio by I-123 mIBG in patients with noni- schemic heart failure . Spatial dyssynchrony was worse in patients with H/M ratio < 2 but no differences in temporal dyssynchrony existed. Specific cutoffs of I-123 mIBG as used in our study were not evaluated. In another study looking at echocardiographic dyssynchrony and H/M ratio by I-123 mIBG  Overall dyssyn- chrony was present more in patients with lower compared to higher H/M ratios. Interestingly those with dys- synchrony and H/M ratio >1.6 had better CRT response than those without dyssynchrony but with H/M ratio < 1.6 . An important substudy done in the ADMIRE HF trial was a dysynchrony analysis looking at 92 sudden cardiac death events in the primary trial over a period of 17 month of follow-up. A propensity matched control group
10 Read more
Methods: We included 18 patients with parkinsonism who were referred to one of the two participating molecular imaging facilities for the evaluation of cardiac sympathetic innervation by MIBG scintigraphy. Two consecutive planar image datasets were acquired with LE and ME collimators at 4 h after MIBG administration. Linear regression analyses were performed to describe the association between the H/M ratios gained with both collimator settings, and the accuracy of a linear transfer of the H/M ratio between collimators and across centers was assessed using a leave- one-out procedure.
Our results complement a recent study showing that macrophages in the intestinal muscularis polarize towards a more anti-inflammatory, tissue-protective macrophage after adrenergic β2 receptor activation (Gabanyi et al. 2016). Additionally, our work is in line with increasing recognition that the sympathetic ner- vous system is crucial to regulate the immune re- sponse targeting lymphoid organs. Earlier work showed that the anti-inflammatory effect of the vagus nerve depends on the spleen and in its sympathetic innervation (Huston et al. 2006; Rosas-Ballina et al. 2008; Nance and Sanders 2007; Bratton et al. 2012). Furthermore, it is suggested that the sympathetic splanchnic nerve is necessary for the cholinergic anti-inflammatory pathway and interaction with the spleen (Martelli et al. 2014). Another study showed that the sympathetic nervous system controls lympho- cyte egress from lymph nodes and numbers of circu- lating lymphocytes (Nakai et al. 2014). Furthermore, catecholamines increase migration and proliferation potential of myeloid precursor cells from bone mar- row (Spiegel et al. 2007).
18 Read more
first observed at low magnification (40 × ), to locate “hot spots”, that is, regions containing the highest density of posi- tive sympathetic nerve fibers. Then, 3–5 high-magnification (100 × ) microscopic fields were randomly chosen from the “hot spots” to estimate the positive nerve areas. The posi- tive nerve areas of each field were measured and calculated using Image-Pro Plus v6.0 software (Media Cybernetics, Inc., Bethesda, MD, USA). In contrast, the β 2-AR expres- sion levels were estimated based on the integrated optical density (IOD), which was measured using Image-Pro Plus v6.0 software. Similar to the measurement process used to study sympathetic innervation, 3–5 high-magnification (100 × ) microscopic fields were randomly chosen from “hot spots” found at a low magnification (40 × ) to estimate the IOD value. The mean IOD value for each field was calculated using the following formula: mean IOD = IOD of positive cells/total areas of the field. 23 Finally, we compared the posi-
21 Read more
Sympathetic innervation of the heart originates in the stellate ganglia. Previous studies have shown that arterial VSMCs mediate proximal sympathetic axon extension by secretion of artemin (Enomoto et al., 2001; Honma et al., 2002), neurotrophin 3 (Francis et al., 1999; Kuruvilla et al., 2004) and endothelins (Makita et al., 2008). Although proximal extension out of the ganglia is well characterized, the mechanisms responsible for distal extension to reach target cells remain elusive. In distal axon extension, nerves adopt a stereotypical pattern in target tissues prior to innervating final target cells. Nerve growth factor (NGF) is required for terminal sympathetic innervation of target tissues (Glebova and Ginty, 2004). Mutants lacking Ngf and Bcl2-associated X protein (Bax) have normal sympathetic axon extension along the extracardiac vasculature but sympathetic innervation is drastically decreased in the heart. This concomitant knockout of the pro-apoptotic factor Bax allows neurons to survive in the absence of NGF, demonstrating that NGF plays a role in distal cardiac sympathetic axon growth that is distinct from its role in survival (Glebova and Ginty, 2004). However, the precise origin and function of NGF during cardiac innervation remain to be examined.
11 Read more
Leukocyte recruitment exhibits circadian, ~24h oscillations, which is dependent on local input by the sympathetic nervous system (SNS). Sympathetic nerves reach tissues alongside arterioles. Since smaller veins are devoid of sympathetic innervation but are the main site of leukocyte recruitment, it is unclear how these adrenergic stimuli reach veins to regulate leukocyte infiltration to tissues. Here, we demonstrate rhythmic differences in the ability of leukocytes to adhere to arteries and veins in an acute inflammatory scenario. Using in vivo quantitative imaging after TNF-α stimulation, we could observe higher leukocyte recruitment in the carotid artery in the morning and lower at night. It was the opposite situation in the case of the jugular vein; lower in the early morning and higher at night. We could confirm the same results in the microvasculature of the cremaster muscle, suggesting an intrinsic mechanism independent on the vessel location. Among different oscillatory cell adhesion molecules, intercellular adhesion molecule 1 (ICAM-1) fitted most closely with the recruitment data. Using genetically modified mice and blocking antibodies, we could confirm the functional importance of ICAM- 1 in these oscillations in both vessels. As the SNS has in important role in rhythmic leukocyte recruitment, we next used pharmacological and surgical procedures for inducing denervation in our mice. We found ablated oscillations in leukocyte recruitment, as well as in Icam1 gene expression. Similar results were obtained when we focused on the β2 adrenergic receptors, via β2-antagonists and Adrb2 -/-
131 Read more
23. Simantirakis EN, Prassopoulos VK, Chrysostomakis SI, Kochiadakis GE, Koukouraki SI, Lekakis JP, et al. Effects of asynchronous ventricular activation on myocardial adrenergic innervation in patientswith permanent dual-chamber pacemakers; an I(123)- metaiodobenzylguanidine cardiac scintigraphic study. Eur Heart J 2001; 22(4): 323-332. https://dx.doi.org/10.1053/euhj.2000.2482. 24. Losik DV, Romanov AB, Shabanov VV, Bairamova SA, Yakubov AA,
OBJECTIVE. Individuals with congenital central hypoventilation syndrome have char- acteristic variants in the PHOX2B gene (primarily polyalanine expansion muta- tions). The PHOX2B gene acts as a transcriptional activator in the promotion of pan-neuronal differentiation in the autonomic nervous system during early em- bryologic development, with a primary role in the sympathetic noradrenergic phenotype in vertebrates. Because sympathetic innervation has been hypothesized to affect the development of dermatoglyphic pattern types, we hypothesized that individuals with PHOX2B-confirmed congenital central hypoventilation syndrome would have characteristic dermatoglyphic patterning and that the dermatoglyphic phenotype would be related to the disease-defining PHOX2B genotype.
DCC expression is detectable in sympa- thetic axon bundles surrounding mesen- teric arteries, but the arterial wall is inner- vated by a subset of DCC-expressing axons, suggesting that some axons innervate arter- ies in response to netrin-1/DCC signaling, while others continue to extend. Further- more, since SMC-specific deletion of Ntn1 only partially lowered netrin-1 levels and arterial innervation was reduced, but not completely abolished in Ntn1 mutants, we cannot exclude that other factors may con- tribute to arterial innervation. Previously identified factors, such as NGF, NTF, and artemin, may participate to this process. Defects in sympathetic outgrowth and alignment with arteries were described in mouse mutants for Ngf, Ntf3, and the arte- min receptor, Ret, but perinatal lethality so far precluded analysis of arterial inner- vation in these mice (38–40). Nevertheless, despite the possible involvement of other factors, partial loss of netrin-1 function was sufficient to induce severe defects in adult artery innervation, functionally leading to loss of vasoconstriction, which was induced by a drop in core body temperature in anesthetized mice. These data show that even a 50% reduction in netrin-1 levels has func- tional consequences on blood flow supply to peripheral organs in stress conditions. SMC-specific Ntn1-deficient mice therefore pres- ent a unique mouse model to study consequences of loss of periph- eral arterial sympathetic innervation on blood pressure control and cardiovascular homeostasis in resting and stress conditions. Figure 4
12 Read more
I-mIBG imaging in several cardiac diseases have noted decreased global cardiac 123 I-mIBG uptake (H/M ratio) in combination with increased global washout. In a variety of different conditions such as congestive heart failure, coronary artery disease, and inherited arrhyth- mias, such changes have been demonstrated to indicate disease progression or an adverse prognosis [8,29-35]. Additionally, pharmaceutical and device therapy in some of these conditions has resulted in recession of these findings [36-38]. The fact that different cardiac diseases are associated with the changes in cardiac up- take or washout of 123 I-mIBG suggests the presence of a common reaction of the cardiac sympathetic nervous system . It has been suggested that one such mech- anism could be a high rate of post-ganglionic cardiac sympathetic traffic whereby the locally increased rate of translocation of neurotransmitter vesicles to the membrane surface and an increased rate of exocytosis result in decreased regional 123 I-mIBG uptake and higher washout. The results of our study point to the development of regional imbalances of sympathetic innervation with either increased regional sympathetic tone (reflected by the increased regional washout) or innervation defects in patients with PAF (paroxysmal atrial fibrillation) both before and after PVI.
10 Read more
this slowed repolarization leads to spatially heterogeneous conduction slowing since conduction velocity is highly sensitive to the maximum diastolic potential. This leads to localized wave break in regions of slowed repolarization. The presence of a heterogeneous distribution of [ACh] exacerbates this effect by amplifying these conduction heterogeneities. In particular, if [ACh] is reduced in a region of tissue, the elevated maxi- mum diastolic potential will induce conduction block in that region during rapid pacing. Once this occurs, the fractionated wave propagates readily in regions of high [ACh] but not in regions of low [ACh]. Taken together, these results suggest that, in the presence of elevated sympathetic tone, the heterogeneous distribution of para- sympathetic innervation, as modeled by heterogeneous [ACh], provides a substrate for wave break and reentry. Frequency-dependent secretion of NGF by atrial myocytes — a likely mechanism underlying global autonomic remodeling in the fibrillating atrium. NGF has been shown to be a key stimulus underlying sprouting of both sympathetic and parasympathetic nerves in the heart (19, 20, 23). Although NGF has been reported to increase in the rapidly paced atrium and also in the human AF atrium, the molecular mechanisms underly- ing this NGF release and the precise cellular source of this NGF have not been previously elucidated. Fur- thermore, it is not known whether there are regional differences in NGF secretion in the fibrillating atrium or whether these regional differences contribute to autonomic and electrophysiological remodeling in AF.
23 Read more
The adult mammalian cochlea receives dual afferent innervation: the inner sensory hair cells are innervated exclusively by type I spiral ganglion neurons (SGN), whereas the sensory outer hair cells are innervated by type II SGN. We have characterized the spatiotemporal reorganization of the dual afferent innervation pattern as it is established in the developing mouse cochlea. This reorganization occurs during the first postnatal week just before the onset of hearing. Our data reveal three distinct phases in the development of the afferent innervation of the organ of Corti: (1) neurite growth and extension of both classes of afferents to all hair cells (E18-P0); (2) neurite refinement, with formation of the outer spiral bundles innervating outer hair cells (P0-P3); (3) neurite retraction and synaptic pruning to eliminate type I SGN innervation of outer hair cells, while retaining their innervation of inner hair cells (P3-P6). The characterization of this developmental innervation pattern was made possible by the finding that tetramethylrhodamine-conjugated dextran (TMRD) specifically labeled type I SGN. Peripherin and choline-acetyltransferase immunofluorescence confirmed the type II and efferent innervation patterns, respectively, and verified the specificity of the type I SGN neurites labeled by TMRD. These findings define the precise spatiotemporal neurite reorganization of the two afferent nerve fiber populations in the cochlea, which is crucial for auditory neurotransmission. This reorganization also establishes the cochlea as a model system for studying CNS synapse development, plasticity and elimination.
The mutations found to cause FD are all located in the ELP1 / IKBKAP gene with the major haplotype consisting of a noncoding point mutation IVS20+6T>C identified in over 99.5% of individuals with the disease (Anderson et al., 2001; Slaugenhaupt et al., 2001). The mutation is located in the donor splice site of intron 20, which weakens the intron-exon boundary and leads to the variable exclusion of exon 20 from spliced transcripts. Exon 20 skipping introduces a nonsense mutation that gives rise to a truncated Elp1 protein (Elp1 Tr ) that is rapidly degraded (Slaugenhaupt et al., 2001). For poorly understood reasons that may relate to differences in splicing fidelity, the ratio of normal-to- mutant ELP1 mRNA varies across cell types and is particularly low in peripheral sensory and sympathetic neurons in individuals with FD (Cuajungco et al., 2003; Slaugenhaupt et al., 2001). The relatively low levels of Elp1 protein in sympathetic and sensory neurons correlate with early postmortem studies of individuals with FD who showed dramatic reduction in the number of sensory, sympathetic and some parasympathetic neurons (Axelrod et al., 1981; Pearson and Pytel, 1978; Pearson et al., 1978). The physiological impairments caused by sensory and sympathetic neuron loss are present from birth and appear to progress with age, but how Elp1 functions and whether it is required in adult neurons remains unknown.
10 Read more