Small Fiber Polyneuropathy May Be a Nexus Between Autonomic Nervous System Dysregulation and Pain in Interstitial Cystitis/Bladder Pain Syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a highly heterogeneous chronic and debilitating condition which effects millions of women and men in the United States. While primarily defined by urinary symptoms and pain perceived to be emanating from the bladder, IC/BPS patients frequently have co-occurring conditions and symptoms, many of which affect diverse body systems related to autonomic nervous system function. The impact on the autonomic system appears to stem from increased sympathetic innervation of the urinary tract, along with increased systemic sympathetic tone and decreased parasympathetic tone. Concurrent with these findings is evidence for destruction of peripheral sympathetic innervation to the sweat glands which may relate to small fiber polyneuropathy. It is unknown to what degree the wider alterations in autonomic function are also related to destruction/alterations in the small fibers carrying autonomic innervation. This potential nexus is an important point of investigation to better understand the unclarified pathophysiology of interstitial cystitis/bladder pain syndrome, the numerous co-occurring symptoms and syndromes, and for the identification of novel targeted therapeutic strategies.

Evidence of Ventricular Arrhythmogenicity and Cardiac Sympathetic Hyperinnervation in Early Cirrhotic Cardiomyopathy

Cirrhotic cardiomyopathy (CMP) is associated with altered cardiac electrophysiological (EP) properties, which leads to the risk of ventricular arrhythmias (VAs). We aimed to evaluate the EP properties, autonomic, and structural remodeling in a rabbit model with early liver cirrhosis (LC). Twelve rabbits were assigned to the sham and LC groups. The early-stage LC was induced by the ligation of the common bile duct. All rabbits received an EP study, VA inducibility test, myocardial, and liver histology staining. Western blot analyses of protein expression and tyrosine hydroxylase stain for sympathetic nerves were performed. The effective refractory period the LC group was significantly longer than the sham group [i.e., left ventricle (LV) 205.56 ± 40.30 vs. 131.36 ± 7.94 ms; right ventricle (RV) 206.78 ± 33.07 vs. 136.79 ± 15.15 ms; left atrium (LA) 140.56 ± 28.75 vs. 67.71 ± 14.29 ms; and right atrium (RA) 133.78 ± 40.58 vs. 65.43 ± 19.49 ms, all p < 0.01], respectively. The VA inducibility was elevated in the LC group when compared with the sham group (i.e., 21.53 ± 7.71 vs. 7.76 ± 2.44%, p = 0.013). Sympathetic innervation (102/μm2/mm2) was increased in all cardiac chambers of the LC group compared with the sham group (i.e., LV 9.11 ± 4.86 vs. 0.17 ± 0.15, p < 0.01; RV 4.36 ± 4.95 vs. 0.18 ± 0.12, p = 0.026; LA 6.79 ± 1.02 vs. 0.44 ± 0.20, p = 0.018; and RA 15.18 ± 5.12 vs. 0.10 ± 0.07, p = 0.014), respectively. Early LC is presented with an increased ventricular vulnerability, structural heterogeneity, and sympathetic innervation. Close monitoring for fatal arrhythmias is warranted in patients with early stages of LC.

Influence of characteristics of epicardial adipose tissue and myocardial sympathetic innervation on the development of late recurrence of atrial fibrillation after radiofrequency ablation

Aim. To investigate the relationship between radiological characteristics of epicardial adipose tissue (EAT) and myocardial sympathetic activity, as well as to study their association with late recurrence of atrial fibrillation (AF) after radiofrequency ablation (RFA).Material and methods. This prospective study included 26 people with persistent and long-standing persistent AF scheduled for interventional AF treatment. Before the RFA procedure, all patients underwent cardiac 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy to assess the myocardial sympathetic innervation and contrast-enhanced cardiac multislice computed tomography to assess pulmonary vein anatomy, left atrial volume, and EAT volume. Clinical follow-up, including 12-lead electrocardiography (ECG) and 24-hour ECG monitoring, was carried out 3, 6 and 12 months after RFA.Results. After the end of follow-up, the patients were divided into two groups: with AF recurrence (group 1, n=8) and without AF recurrence (group 2, n=18). Multivariate logistic analysis found that only the 123I-MIBG washout rate (odds ratio, 1,0943; 95% confidence interval, 1,0138-1,1812) proved to be an independent predictor of late AF recurrence after RFA. ROC analysis revealed that a 123I-MIBG washout rate >21% with a sensitivity of 75% and a specificity of 83,3% (AUC=0,844; p<0,001) predicts late AF recurrence after RFA.Conclusion. Parameters of myocardial sympathetic activity, assessed by 123I-MIBG myocardial scintigraphy, are associated with late AF recurrence after RFA in patients with persistent and long-standing persistent AF. There were no reliable data confirming associations between myocardial sympathetic innervation and radiological EAT indicators, as well as the effect of the latter on the risk of AF recurrence after RFA.

Abstract 16831: Provoked PFO Shunt And Posterior Circulation Stroke: An Underrecognized Association

Case Presentation: A 50 year old man presented with nausea and weakness. MRI brain showed a small acute infarct in the right pons. CT angiography of the head and neck was unremarkable. No thrombus, vegetation, or inter-atrial communication was seen on transthoracic echocardiogram: LVEF was 55-60% with normal left atrial size. No history of atrial fibrillation, hypertension, diabetes or drug abuse was reported; lower extremity duplex was negative for deep venous thrombosis. TSH was normal. Transesophageal echocardiography showed an aneurysmal atrial septum: agitated saline injection did not demonstrate an inter-atrial communication (figure 1). Repeat saline injection during the same procedure with Valsalva maneuver demonstrated a moderate-sized, provoked right-to-left, patent foramen ovale (PFO) shunt (figure 2). Discussion: Physiologically decreased sympathetic innervation spares posterior cerebral circulation from Valsalva-induced vasoconstriction. The disproportionate increase in posterior cerebral blood flow when venous return/cardiac output increases in the immediate post-strain period explains the association of provoked PFO shunt and paradoxical embolism to posterior circulation. Although the association has been described in literature, it remains underappreciated. Recognition of the association expedited secondary prevention of stroke in this non-elderly patient by circumventing the need to exclude atrial fibrillation on ambulatory rhythm monitoring (3-6 months) before referral for PFO closure.

Intrauterine L-NAME Exposure Weakens the Development of Sympathetic Innervation and Induces the Remodeling of Arterial Vessels in Two-Week-Old Rats

Nitric oxide (NO) has been shown to stimulate differentiation and increase the survival of ganglionic sympathetic neurons. The proportion of neuronal NOS-immunoreactive sympathetic preganglionic neurons is particularly high in newborn rats and decreases with maturation. However, the role of NO in the development of vascular sympathetic innervation has never been studied before. We tested the hypothesis that intrauterine NO deficiency weakened the development of vascular sympathetic innervation and thereby changed the contractility of peripheral arteries and blood pressure level in two-week-old offspring. Pregnant rats consumed NOS inhibitor L-NAME (250 mg/L in drinking water) from gestational day 10 until delivery. Pups in the L-NAME group had a reduced body weight and blood level of NO metabolites at 1–2 postnatal days. Saphenous arteries from two-week-old L-NAME offspring demonstrated a lower density of sympathetic innervation, a smaller inner diameter, reduced maximal active force and decreased α-actin/β-actin mRNA expression ratio compared to the controls. Importantly, pups in the L-NAME group exhibited decreased blood pressure levels before, but not after, ganglionic blockade with chlorisondamine. In conclusion, intrauterine L-NAME exposure is followed by the impaired development of the sympathetic nervous system in early postnatal life, which is accompanied by the structural and functional remodeling of arterial blood vessels.

3D-mapping of human lymph node and spleen reveals integrated neuronal, vascular, and ductal cell networks

As secondary lymphoid organs, the spleen and lymph node represent important hubs for both innate and adaptive immunity. Neuroanatomical and tracing data, largely derived from rodents, suggest that lymph nodes contain sensory and sympathetic innervation, whereas the spleen contains postganglionic sympathetic innervation, with conflicting views regarding the existence of cholinergic or vagal innervation. Herein, we map the neuronal, vascular, and sinus cell networks from human spleen and lymph node using highly multiplexed CODEX (CO-Detection by indEXing) and 3D light sheet microscopy of cleared tissues. These data demonstrate striking delineation of two distinct layers within the lymph node subcapsular sinus-the ceiling defined by Podoplanin expression and floor by LYVE1, which overlays the lymph node follicles. Within the lymph node interior, we observed a mesh-like vessel network innervated with GAP43 and beta3-tubulin. Dense perivascular innervation occurred in both tissues, including a subset of axonal processes expressing choline acetyl transferase (ChAT). Four neuronal markers (ChAT, PGP9.5, tyrosine hydroxylase, and beta3-tubulin) localized to the arterial tunica externa suggest expression in the nervi vasorum while GAP43 was expressed within the internal elastic membrane of arteries. These data represent highly novel 3D visualization of perivascular and periductal autonomic innervation within these two key human organs.

Age-Related Variation in Sympathetic Nerve Distribution in the Human Spleen

Introduction: The cholinergic anti-inflammatory pathway (CAIP) has been proposed as an efferent neural pathway dampening the systemic inflammatory response via the spleen. The CAIP activates the splenic neural plexus and a subsequent series of intrasplenic events, which at least require a close association between sympathetic nerves and T cells. Knowledge on this pathway has mostly been derived from rodent studies and only scarce information is available on the innervation of the human spleen. This study aimed to investigate the sympathetic innervation of different structures of the human spleen, the topographical association of nerves with T cells and age-related variations in nerve distribution.Materials and Methods: Spleen samples were retrieved from a diagnostic archive and were allocated to three age groups; neonates, 10–25 and 25–70 years of age. Sympathetic nerves and T cells were identified by immunohistochemistry for tyrosine hydroxylase (TH) and the membrane marker CD3, respectively. The overall presence of sympathetic nerves and T cells was semi-automatically quantified and expressed as total area percentage. A predefined scoring system was used to analyze the distribution of nerves within different splenic structures.Results: Sympathetic nerves were observed in all spleens and their number appeared to slightly increase from birth to adulthood and to decrease afterward. Irrespective to age, more than halve of the periarteriolar lymphatic sheaths (PALSs) contained sympathetic nerves in close association with T cells. Furthermore, discrete sympathetic nerves were observed in the capsule, trabeculae and red pulp and comparable to the total amount of sympathetic nerves, showed a tendency to decrease with age. No correlation was found between the number of T cells and sympathetic nerves.Conclusion: The presence of discrete sympathetic nerves in the splenic parenchyma, capsule and trabecular of human spleens could suggest a role in functions other than vasoregulation. In the PALS, sympathetic nerves were observed to be in proximity to T cells and is suggestive for the existence of the CAIP in humans. Since sympathetic nerve distribution shows interspecies and age-related variation, and our general understanding of the relative and spatial contribution of splenic innervation in immune regulation is incomplete, it remains difficult to estimate the anti-inflammatory potential of targeting splenic nerves in patients.