Blocking Ocular Sympathetic Activity Inhibits Choroidal Neovascularization

Purpose: To investigate how modulating ocular sympathetic activity affects progression of choroidal neovascularization (CNV), a hallmark feature of wet age-related macular degeneration (AMD).Methods: In the first of two studies, Brown Norway rats underwent laser-induced CNV and were assigned to one of the following groups: daily eye drops of artificial tears (n = 10; control group); daily eye drops of the β-adrenoreceptor agonist isoproterenol (n = 10); daily eye drops of the β-adrenoreceptor antagonist propranolol (n = 10); sympathetic internal carotid nerve (ICN) transection 6 weeks prior to laser-induced CNV (n = 10). In the second study, rats underwent laser-induced CNV followed by ICN transection at different time points: immediately after the laser injury (n = 6), 7 days after the laser injury (n = 6), and sham surgery 7 days after the laser injury (n = 6; control group). All animals were euthanized 14 days after laser application. CNV development was quantified with fluorescein angiography and optical coherence tomography (in vivo), as well as lesion volume analysis using 3D confocal reconstruction (postmortem). Angiogenic growth factor protein levels in the choroid were measured with ELISA.Results: In the first study, blocking ocular sympathetic activity through pharmacological or surgical manipulation led to a 75% or 70% reduction in CNV lesion volume versus the control group, respectively (P < 0.001). Stimulating ocular sympathetic activity with isoproterenol also led to a reduction in lesion volume, but only by 27% versus controls (P < 0.05). VEGF protein levels in the choroid were elevated in the three treatment groups (P < 0.01). In the second study, fluorescein angiography and CNV lesion volume analysis indicated that surgically removing the ocular sympathetic supply inhibited progression of laser-induced CNV, regardless of whether ICN transection was performed on the same day or 7 days after the laser injury.Conclusion: Surgical and pharmacological block of ocular sympathetic activity can inhibit progression of CNV in a rat model. Therefore, electrical block of ICN activity could be a potential bioelectronic medicine strategy for treating wet AMD.

Autonomic Nervous System Function in Newly Diagnosed Multiple Sclerosis: Association With Lipid Levels and Insulin Resistance

Autonomic nervous system (ANS) disorders are common in multiple sclerosis (MS). Previous studies showed differences in insulin resistance (IR) and lipoprotein levels in MS subjects compared to controls. Lipolysis caused by increased sympathetic activity could be one of the possible linking mechanisms leading to dyslipidemia in MS. Our study aimed to evaluate ANS activity in the context of glucose and lipid metabolism in people with MS. We prospectively measured short-term heart rate variability (HRV), fasting lipoprotein concentrations, and calculated IR indices based on plasma glucose and insulin levels during oral glucose tolerance test (oGTT) in 32 patients with MS and 29 healthy controls matched for age, sex and body mass index in our study. There was no significant difference in HRV parameters and lipoprotein levels between MS and controls. A significant positive correlation was found between low/high-frequency power ratio (LF/HF) and triglycerides (r=0.413, p=0.021) in MS subjects but not in controls. A significantly lower whole-body insulin sensitivity index (ISIMat) was found in patients with MS compared to the control group (7.3±3.7 vs. 9.8±5.6, p=0.041). No significant correlations were found between LF/HF and IR parameters. In MS subjects, the positive correlation of LF/HF with triglycerides could reflect the effects of sympathetic activity on lipolysis. Positive correlations of sympathetic activity with increased lipoprotein levels could rather reflect processes associated with immune system activation/inflammation, than processes involved in glucose homeostasis maintenance.

Obstructive sleep apnea and cardiovascular comorbidity: modern discordance in assessing the effectiveness of CPAP-therapy against the pathogenetic mechanisms and cardiovascular diseases

Sleep-disordered breathing (and obstructive sleep apnea, OSA) is a common pathology in the general population in economically developed countries. In the last decades, CPAP therapy (continuous positive airway pressure) became the first-choice treatment option in clinically relevant OSA.Objective. The review summarized available evidence about the effects of CPAP-therapy on the main pathogenetic pathways of OSA (sleep-related sympathetic activity, vascular inflammation, endothelial dysfunction, oxidative stress, and blood coagulation) and cardiovascular diseases (CVDs - hypertension, cardiac arrhythmias, heart failure, pulmonary hypertension, coronary heart disease, and combined cardiovascular outcomes, including cardiovascular mortality).Methods. We analyzed the data of the randomized observational cohort clinical trials and metaanalyses, which assessed the effects of CPAP-therapy on the pathophysiological mechanisms of OSA and the associated CVDs. We also analyzed current guidelines on the management of patients with CVDs and OAS. We searched the following databases: Scopus, Pubmed, Google Scholar, Russian Scientific Citation Index.Results. Despite the rather recent implementation of this method, the accumulated evidence shows its favorable impact on OSA pathogenesis (on sympathetic activity and, to some extent, on vascular inflammation and endothelial dysfunction) and CVDs (hypertension, in particular, resistant hypertension, and paroxysmal atrial fibrillation). The observational studies also demonstrate favorable outcomes regarding other CVDs. However, the data of the randomized clinical trials are limited or controversial, the samples are rather small, which leads to inconsistent conclusions.Conclusion. Currently, most of the researchers emphasize that the required CPAP-adherence level (regular use for at least 4 h nightly) is the main barrier to getting the high-level evidence of CPAP efficiency with regard to the cardiovascular risk. This factor becomes the biggest limitation in patients who are characterized by the low compliance because they are not prone to daytime sleepiness.

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.

P105 Endocrine, autonomic and vascular function in children with Sleep Disordered Breathing

SDB is a risk factor for cardiovascular disease and co-exists with chronic endocrine disorders such as type II diabetes and metabolic syndrome. Children with SDB have increased blood flow velocity, an indicator of reduced vascular compliance and early vascular aging. Increased blood flow velocity is positively associated with sympathetic activity, increased arterial sympathetic nerve fibre density and endothelial damage. Whether changes in endocrine function occur concomitantly with altered autonomic and vascular function in children with SDB was assessed. Thirty six children scheduled for tonsillectomy underwent overnight polysomnography (SDB severity), pupil light reflex (autonomic function), fasting brachial artery blood flow assessment (vascular function - Doppler Ultrasound). Leptin and Ghrelin - both hormonal markers associated with sympathetic activity were measured in urine using ELISA and serum using MagPlex. The following dimensions of the dorsal lingual artery (tonsil) were measured – medial thickness, medial area, smooth muscle cell number/layers. We observed a positive correlation between serum and urine leptin and ghrelin concentrations. Increased blood flow velocity and arterial medial thickness were both associated with increased serum and urine leptin and ghrelin concentrations. Pupil light reflex was negatively associated with serum leptin and ghrelin levels. OAHI was positively correlated with leptin and ghrelin concentration (urine and serum) but not blood flow velocity. Blood flow velocity was inversely correlated with SpO2 nadir (REM). Our findings suggest that SDB has a global effect on the autonomic, vascular and endocrine systems.The impact of untreated paediatric SDB on the development of comorbidities in later life needs urgent attention.

Cardiac Sympathetic Activity and Rhythm Control Following Pulmonary Vein Isolation in Patients with Paroxysmal Atrial Fibrillation—A Prospective 123I-mIBG-SPECT/CT Imaging Study

Background: Pulmonary vein isolation (PVI) and antiarrhythmic drug therapy are established treatment strategies to preserve sinus rhythm in atrial fibrillation (AF). However, the efficacy of both interventional and pharmaceutical therapy is still limited. Solid evidence suggests an important role of the cardiac sympathetic nervous system in AF. In this blinded, prospective observational study, we studied left ventricular cardiac sympathetic activity in patients treated with PVI and with antiarrhythmic drugs. Prospectively, Iodine-123-benzyl-guanidine single photon emission computer tomography (123I-mIBG-SPECT) was performed in a total of 23 patients with paroxysmal AF, who underwent PVI (n = 20) or received antiarrhythmic drug therapy only (n = 3), respectively. 123I-mIBG planar and SPECT/CT scans were performed before and 4 to 8 weeks after PVI (or initiation of drug therapy, respectively). For semiquantitative SPECT image analysis, attenuation-corrected early/late images were analyzed. Quantitative SPECT analysis was performed using the AHA 17-segment model of the left ventricle. Results: PVI with point-by-point radiofrequency ablation led to a significantly (p < 0.05) higher visual sympathetic innervation defect score when comparing pre-and post PVI. Newly emerging innervation deficits post PVI were localized predominantly in the inferior lateral wall. These findings were corroborated by semiquantitative SPECT analysis identifying inferolateral segments with a reduced tracer uptake in comparison to SPECT before PVI. Following PVI, patients with an AF relapse showed a different sympathetic innervation pattern compared to patients with sufficient rhythm control. Conclusions: PVI results in novel defects of cardiac sympathetic innervation. Differences in cardiac sympathetic innervation remodelling following PVI suggest an important role of the cardiac autonomous nervous system in the maintenance of sinus rhythm following PVI.