Cardiac Autonomic Innervation Research Articles

The autonomic nerves around the vein of Marshall: apostmortem study with clinical implications.

This study aims to analyze the vein of Marshall (VOM) in human autopsy hearts and its correlation with clinical data to elucidate the morphological substrates of atrial fibrillation (AF) and other cardiac diseases. Twenty-three adult autopsy hearts were studied, assessing autonomic nerves by immunohistochemistry with tyrosine hydroxylase (sympathetic nerves), choline acetyltransferase (parasympathetic nerves), growth-associated protein 43 (neural growth), and S100 (general neural marker) antibodies. Interstitial fibrosis was assessed by Masson trichrome staining. Measurements were conducted via morphometric software. The results were correlated with clinical data. Sympathetic innervation was abundant in all VOM-adjacent regions. Subjects with a history of AF, cardiovascular cause of death, and histologically verified myocardial infarction had increased sympathetic innervation and neural growth around the VOM at the mitral isthmus. Interstitial fibrosis increased with age and heart weight was associated with AF and cardiovascular cause of death. This study increases our understanding of the cardiac autonomic innervation in the VOM area in various diseases, offering implications for the development of new therapeutic approaches targeting the autonomic nervous system.

Baroreflex activity change after pulmonary vein isolation in patients with atrial fibrillation

Aim. To study the intraprocedural changes in baroreflex activity after catheter pulmonary vein isolation in paroxysmal atrial fibrillation patients.Methods. From October 2021 to June 2022, sinus rhythm was registered at the start of procedure in 21 patients with paroxysmal atrial fibrillation admitted for catheter pulmonary vein isolation. Patients before and after procedure were tested with phenylephrine. Pre- and postoperative baroreflex activity and sinus rhythm rate were analyzed.Results. After catheter pulmonary vein isolation, the baroreflex activity decreased from 5.8 [3.5; 11.3] ms/mmHg to 0.3 [-0.1; 1.8] ms/mmHg, р<0.001, based on systolic arterial pressure, and from 9.5 [5.1; 15.5] ms/mmHg to 0.6 [0; 7.6] ms/mmHg, p=0.033, based on diastolic arterial pressure.Conclusion. Intraprocedural phenylephrine test allows to study the baroreflex activity changes and to assess the modification of cardiac autonomic innervation.

Mapping the functional anatomy and topography of the cardiac autonomic innervation for selective cardiac neuromodulation using MicroCT.

Background: Vagus nerve stimulation (VNS) has gained great importance as a promising therapy for a myriad of diseases. Of particular interest is the therapy of cardiovascular diseases, such as heart failure or atrial fibrillation using selective cardiac VNS. However, there is still a lack of organ-specific anatomical knowledge about the fascicular anatomy and topography of the cardiac branch (CB), which diminishes the therapeutic possibilities for selective cardiac neuromodulation. Here, we established a topographical and anatomical map of the superior cardiac VN in two animal species to dissect cervical and cardiac VN morphology. Methods: Autonomic nerves including superior CBs were harvested from domestic pigs and New Zeeland rabbits followed by imaging with microcomputed tomography (µCT) and 3D rendering. The data were analyzed in terms of relevant topographical and anatomical parameters. Results: Our data showed that cardiac vagal fascicles remained separated from other VN fascicles up to 22.19 mm (IQR 14.02–41.30 mm) in pigs and 7.68 mm (IQR 4.06–12.77 mm) in rabbits from the CB point and then started merging with other fascicles. Exchanges of nerve fascicles between sympathetic trunk (ST) and VN were observed in 3 out of 11 nerves, which might cause additional unwanted effects in unselective VNS. Our 3D rendered digital model of the cardiac fascicles was generated showing that CB first remained on the medial side where it branched off the VN, as also shown in the µCT data of 11 pig nerves, and then migrated towards the ventromedial site the further it was traced cranially. Conclusion: Our data provided an anatomical map of the cardiac vagal branches including cervical VN and ST for future approaches of selective cardiac neurostimulation, indicating the best position of selective cardiac VNS just above the CB point.

Autonomic disorders and myocardial 123I-metaiodobenzylguanidine scintigraphy in Huntington’s disease

BackgroundHuntington’s disease (HD) patients often present with abnormal modulation of blood pressure and heart rate. We investigated whether cardiac autonomic innervation assessed by 123I-metaiodobenzylguanidine (MIBG) imaging is impaired in HD patients, in comparison with controls (Ctrl). MethodsFifteen patients (6 F and 9 M) were assessed by the motor section of the Unified HD Rating Scale, the Total Function Capacity, and the scale for outcomes in Parkinson’s disease-autonomic (SCOPA-AUT) questionnaire. All patients and 10 Ctrl (5 F and 5 M) underwent 123I-MIBG imaging. From planar images, the early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates (WR) were calculated. ResultsWe did not find significant differences in early and late H/M ratios and WR between the two groups. At individual level, three patients showed reduced early and/or late H/M ratios. The most common autonomic complaints were gastrointestinal and genitourinary disorders. SCOPA-AUT questionnaire score results positively correlated with the disease duration and WR. ConclusionsOur study indicates that myocardial postganglionic sympathetic innervation is essentially preserved or only minimally involved in HD. These findings suggest that the cardiovascular dysfunction might be mainly due to the impairment of brain areas associated with the regulation and modulation of the heart function.

Asymmetry and Heterogeneity: Part and Parcel in Cardiac Autonomic Innervation and Function.

The cardiac autonomic nervous system (cANS) regulates cardiac adaptation to different demands. The heart is an asymmetrical organ, and in the selection of adequate treatment of cardiac diseases it may be relevant to take into account that the cANS also has sidedness as well as regional differences in anatomical, functional, and molecular characteristics. The left and right ventricles respond differently to adrenergic stimulation. Isoforms of nitric oxide synthase, which plays an important role in parasympathetic function, are also distributed asymmetrically across the heart. Treatment of cardiac disease heavily relies on affecting left-sided heart targets which are thought to apply to the right ventricle as well. Functional studies of the right ventricle have often been neglected. In addition, many principles have only been investigated in animals and not in humans. Anatomical and functional heterogeneity of the cANS in human tissue or subjects is highly valuable for understanding left- and right-sided cardiac pathology and for identifying novel treatment targets and modalities. Within this perspective, we aim to provide an overview and synthesis of anatomical and functional heterogeneity of the cANS in tissue or subjects, focusing on the human heart.

Autonomic cardiac innervation: impact on the evolution of arrhythmias in inherited cardiac arrhythmia syndromes.

The autonomic nervous system (ANS) is an essential component of arrhythmogenicity, especially in the absence of structural heart disease and channelopathy. In this article, the authors review the role and characteristics of ANS in various channelopathies. Some of these, such as most long QT syndromes and catecholaminergic polymorphic ventricular tachycardia, are highly dependent on sympathetic activation, while parasympathetic tone is an important factor for arrhythmias in other channelopathies such as Brugada syndrome or early repolarisation syndrome. Recent advances highlighting the subtle role of ANS in channelopathies are presented here, demonstrating that all is far from being so simple and straightforward and revealing some paradoxical behaviours of channelopathies in relation to discrete ANS imbalance.

The Impact of Omega‐3 Fatty Acids on Cardiac Autonomic Nerve Fiber Innervation in High Fat‐Fed Mice

Peripheral neuropathy and cardiac autonomic neuropathy (CAN) are common and serious complications of diabetes, characterized by loss of peripheral nerves that innervate the skin and loss of parasympathetic and sympathetic nerves that innervate the heart, respectively. CAN is associated with increased risk of myocardial infarction and mortality, yet often goes undetected in patients. Both prediabetic and diabetic patients develop peripheral neuropathy and CAN, suggesting that the level of hyperglycemia at which peripheral neuropathy and CAN develop precedes the onset of diabetes. Although evidence from human and rodent studies indicate that omega-3-fatty acids prevent and/or reverse the development of peripheral neuropathy, the effects of omega-3-fatty acids on CAN has not been investigated. PURPOSE Assess the effects of omega-3-fatty acids on cardiac autonomic nerve fiber innervation in high fat diet-induced prediabetic mice. We hypothesize that omega-3 fatty acids will attenuate a reduction in cardiac autonomic nerve fiber innervation in high fat-fed mice. METHODS Male C57BL/6 mice were randomized into four diet groups (n = 12-14/group) for 14 weeks: 10% low fat fish oil (LFFO), 54% high fat-fish oil (HFFO), 10% low fat-lard (LFL), or 54% high fat-lard (HFL). The von Frey behavioral test for hindpaw mechanical sensitivity was used to characterize peripheral neuropathy at baseline then biweekly for 14 weeks. At study completion, fasting glucose and insulin values were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR). Mice were anesthetized, transcardially perfused with 1% PBS, and heart tissue was harvested and frozen in O.C.T. Heart was sectioned in three planes (anterior coronal, posterior coronal, and sagittal) and mounted on slides. Fluorescence immunohistochemistry was performed on heart cryosections using anti-choline acetyl-transferase and anti-tyrosine hydroxylase followed by Alexa Fluor secondary antibodies to visualize parasympathetic and sympathetic nerve fibers. For each mouse, nerve fibers were quantified on three slides (1 from each plane) and at least 3 areas with the highest nerve fiber density for each slide were examined. Nerve fiber density was determined using Nikon Elements and was calculated as the total length of all counted nerve fibers divided by the total area examined (µm/mm2). RESULTS Body weight, fasting insulin and glucose, and HOMA-IR were higher in HFL compared to all other groups. Fasting glucose was also higher in LFL compared to LFFO. Hindpaw withdrawal threshold was lower in HFL compared to HFFO, indicative of hindpaw hypersensitivity in HFL. CONCLUSIONS Omega-3 fatty acids prevented excess body weight, insulin resistance, elevated glucose, and hindpaw hypersensitivity in mice fed a high fat diet. Based on this data, we expect a diet rich in omega-3 fatty acids will attenuate cardiac autonomic nerve fiber denervation. Taken together, these findings would suggest that omega-3 fatty acids might hold therapeutic potential in the prevention of metabolic derangements as well as peripheral and CAN in individuals who consume a high fat, high calorie diet.

Ultrahigh-Frequency Echocardiography of Autonomic Devoid Phox2B Homozygous Embryos Does Not Reveal a Significant Cardiac Phenotype before Embryo Death

In vivo micro-imaging of mice is useful in studying the genetic basis of cardiac development in mutant embryos. We examined Phox2b–/– mutant mice, which lack autonomic innervation to the heart and die in utero, and investigated whether this lack of innervation causes cardiac dysfunction during embryogenesis. A VisualSonics Vevo 2100 ultrahigh-frequency linear array ultrasound machine with 30- and 40-MHz probes was used to analyze embryo size, gross characteristics, ventricular contractility and rhythm. Phox2b–/– mutant embryos underwent cessation of heartbeat and death at a greater rate than wild-type controls. We did not observe a hydrops phenotype or congenital heart defects in Phox2b–/– mutants. Analysis of heart rhythm revealed no significant correlation with genotype. Absent these signs of a progressive pathology, we suggest that Phox2b–/– mutant embryos likely die of sudden death secondary to acute arrhythmia. These data provide insight into the role of cardiac autonomic innervation during development.

Human adult cardiac autonomic innervation: Controversies in anatomical knowledge and relevance for cardiac neuromodulation.

Cardiac sympathetic blockade is a therapeutic approach for arrhythmias and heart failure and may be a beneficial effect of high thoracic epidural anesthesia. These treatments require detailed knowledge of the spatial location and distribution of cardiac autonomic nerves, however, there are controversies on this subject in humans. To provide a systematic overview of current knowledge on human anatomy of the cardiac autonomic nervous system. In contrast to the often claimed assumption that human preganglionic sympathetic cardiac neurons originate mainly from thoracic spinal segments T1-T4 or T5, there is ample evidence indicating involvement of cervical spinal segment C8 and thoracic spinal segments below T5. Whether cervical ganglia besides the stellate ganglion play a role in transmission of cardiac sympathetic signals is unclear. Similarly, there is debate on the origin of cardiac nerves from different thoracic ganglia. Most human studies report thoracic cardiac nerves emerging from the first to fourth thoracic paravertebral ganglia; others report contributions from the fifth, sixth and even the seventh thoracic ganglia. There is no agreement on the precise composition of nerve plexuses at the cardiac level. After years of debate, it is generally accepted that the vagal nerve contributes to ventricular innervation. Vagal distribution appears higher in atria, whereas adrenergic fibers exceed the number of vagal fibers in the ventricles. Anatomy of the human cardiac autonomic nervous system is highly variable and likely extends beyond generally assumed boundaries. This information is relevant for thoracic epidural anesthesia and procedures targeting neuronal modulation of cardiac sympathetic innervation.

P5392Epicardium derived cells promote sympathetic ganglionic outgrowth towards myocardium in vitro

Abstract Background The autonomic nerve system is essential to maintain homeostasis in the body. In the heart, autonomic innervation is important for adjusting the physiology to the continuously changing demands such as stress responses. After cardiac damage, excessive neurite outgrowth, referred to as autonomic hyperinnervation, can occur which is related to ventricular arrhythmias and sudden cardiac death. The cellular basis for this hyperinnervation is as yet unresolved. Here we hypothesize a role for epicardium derived cells (EPDCs) in stimulating sympathetic neurite outgrowth. Purpose To investigate the potential role of adult EPDCs in promoting sympathetic ganglionic outgrowth towards adult myocardium. Method Fetal murine superior cervical ganglia were dissected and co-cultured with activated adult mesenchymal epicardium-derived cells (EPDCs) or/and adult myocardium in a 3D collagen gel culture system. Four experiment groups were included: Group 1: Vehicle cultures (ganglia cultured without EPDC/myocardium) (n=48); Group 2: ganglia co-cultured with EPDCs (n=38); Group 3: ganglia co-cultured with myocardium (n=95); and group 4: ganglia co-cultured with both EPDCs and myocardium (n=96). The occurrence of neurite outgrowth was assessed in each group. The density of neurites that showed directional sprouting (i.e. sprouting towards myocardium) was assessed as well with a semi-automatic quantification method. Finally, sub-analyses were made by taking gender into account. Results Cervical ganglia cultured with EPDCs alone (group 2) showed increased neurite outgrowth compared to vehicle cultures (group 1), however the neurites did not show directional sprouting towards EPDCs. When co-cultured with myocardium (group 3), directional neurite outgrowth towards myocardium was observed. Compared to the ganglia-myocardium co-cultures, directional outgrowth was significantly increased in co-cultures combining myocardium and EPDCs (group 4), and the neurite density was also significantly augmented. Comparison between males and female ganglia demonstrated that more neurite outgrowth occurred in female-derived ganglia than in male-derived ganglia under the same co-culture conditions. Conclusion Activated adult EPDCs promote sympathetic ganglionic outgrowth in vitro. Sex differences exist in the response of ganglia to EPDCs, and female-derived ganglia appear more sensitive to EPDC-signalling. Results support a role of EPDCs in cardiac autonomic innervation and open avenues for exploring of their role in ventricular hyperinnervation after cardiac damage.

Correlation between sonographic morphology and function of the cervical vagus nerves.

The heart receives parasympathetic and to a lesser degree sympathetic input via the vagus nerve. Here, we investigated whether morphological changes of the cervical vagus nerves (VN) as assessed by high-resolution ultrasound (HRUS) correlated with the autonomic cardiac innervation. Measurement of heart rate variability (HRV) and HRUS of the VNs were performed in 88 healthy subjects (50 female; mean age 56 ± 18 years). HRV parameters and the cross-sectional area (CSA) of the VNs correlated both inversely with age. We also found an inverse correlation between the left VN-CSA and HRV as well as parasympathetic parameters. The results imply an asymmetric parasympathetic (vagal) innervation of the heart.

REM-Sleep Behavior Disorder in Patients With Essential Tremor: What Is Its Clinical Significance?

Objective: REM sleep behavior disorder (RBD) is an important risk factor for the dementia development and for the deterioration of autonomic functions in patients with Parkinson's Disease. RBD has also been reported in patients with Essential Tremor (ET). However, its clinical significance in ET remains still unknown. We aimed to investigate clinical, neuropsychological and cardiac autonomic scintigraphic differences between ET patients with and without RBD.Methods: To assess RBD symptoms, RBD Single-Question has been administered in a cohort of 55 patients with a clinical diagnosis of ET. Patients with clinical RBD underwent polysomnography (PSG) confirmation. All patients completed a battery of neuropsychological assessment of memory, executive function, attention, language, and visuospatial function. Cardiac MIBG scintigraphy was performed in order to measure the cardiac autonomic innervation.Results: Ten ET patients (18%) had a PSG-confirmed RBD (ETRBD+). Compared to ET patients without RBD (ETRBD−), significantly reduced scores on memory domain tests such as Rey auditory verbal learning test immediate recall (p = 0.015) and Rey auditory verbal learning test delayed recall (p = 0.004) and phonemic fluency test (p = 0.028) were present in ETRBD+. By contrast, no other significant clinical difference has emerged from the comparison between two ET groups. Similarly, ETRBD+ patients have cardiac MIBG tracer uptake in the normal value range as occurred in those with ETRBD−.Conclusions: This study improves the knowledge on clinical significance of RBD symptoms in ET patients. Our preliminary findings demonstrate that presence of RBD in ET is associated with neurocognitive impairment, but not with cardiac autonomic dysfunction. Further longitudinal studies are needed to investigate whether ET patients with RBD will develop a frank dementia over the time.

Autonomic Neuromodulation for Preventing and Treating Ventricular Arrhythmias.

The cardiac autonomic nervous system (CANS) is associated with modulation of cardiac electrophysiology and arrhythmogenesis. In this mini review, we will briefly introduce cardiac autonomic anatomy and autonomic activity in ventricular arrhythmias (VAs) and discuss novel approaches of CANS modulation for treating VAs. Studies over the decades have provided a better understanding of cardiac autonomic innervation and revealed overwhelming evidence of the relationship between autonomic tone and VAs. A high sympathetic tone and low parasympathetic (vagal) tone are considered as the major triggers of VAs in patients with myocardial ischemia, which can cause sudden cardiac death. In recent years, novel methods of autonomic neuromodulation have been investigated to prevent VAs, and they have been verified as being beneficial for malignant VAs in animal models and humans. The clinical outcome of autonomic neuromodulation depends on the level of cardiac neuraxis, stimulation parameters, and patient’s pathological status. Since autonomic modulation for VA treatment is still in the early stage of clinical application, more basic and clinical studies should be performed to clarify these mechanisms and optimize autonomic neuromodulation therapies for patients with VAs in the future.

Heart rate variability patterns in anterior st-segment elevation myocardial infarction versus inferior st-segment elevation myocardial infarction patients treated by primary percutaneous coronary intervention

Introduction: Heart rate variability (HRV) has been known as a measurable parameter of the cardiac autonomic function. The cardiac autonomic innervation is heterogeneous and hence leads to different patterns of autonomic modulation. The normal pattern of autonomic modulation is altered in the case of myocardial infarction, the pattern of alteration is not uniform, and it depends on the infarcted wall or region of the heart. Primary percutaneous coronary intervention (PCI) is the gold standard therapy for revascularization of ST-segment elevation myocardial infarction (STEMI) cases, but still conflicting and nonconclusive data are available on the modifications that happen to the cardiac autonomic function after a successful primary PCI with restoration of the Thrombolysis in Myocardial Infarction III flow in the infarct-related artery (IRA). Aim of The Work: Studying and comparing the pattern of autonomic modulation between anterior STEMI patients and inferior STEMI patients. Methods and Results: A total of 93 consecutive patients (56 males and 37 females) presented by STEMI and treated by primary PCI at our cath lab at Ainshams university hospitals (a 24/7 tertiary referral center for primary PCI) during the period between February 2016 and March 2017; 48 had an anterior wall STEMI (ANT) and 45 had an inferior wall STEMI (INF). Mean duration for hospital stay was 4 ± 2 days. Electrocardiogram and respiration were recorded within the day of admission (DA) and at day of discharge (DD). Cardiac autonomic modulation was evaluated using symbolic analysis (SA) of HRV. The first recording for HRV by SA (DA recording) was performed after 18 ± 6 h from primary PCI as soon as the IRA has been opened and the patient stabilized in the cardiac care unit (CCU) for 12 h at least. The second recording for HRV by SA (DD recording) was performed at the DD (duration of admission was 4 ± 2 days). SA recordings showed a significantly predominant of vagal modulation in anterior STEMI patients compared to inferior STEMI at DA, as indicated by 2LV% (10% [7–15] vs. 6% [2–9], P = 0.03). Moreover, at DA, inferior STEMI patients had a significantly higher 0V%, index of sympathetic modulation, compared to anterior STEMI patients (33% [18–47] vs. 19% [12–29], P = 0.02). The second recordings on the DD (DD recording) showed nonsignificant difference between the anterior STEMI and the inferior STEMI groups. Conclusion: After revascularization by primary PCI for STEMI patients, the group presenting by inferior STEMI were characterized by a sympathetic predominance, while those presenting by anterior STEMI were characterized by a predominant vagal modulation. This difference in the sympathetic modulation between the two groups disappeared at the time of discharge from the hospital.

Autonomic Regulation and Ventricular Arrhythmias.

Autonomic nervous system (ANS) has a crucial role of regulating cardiac function in the physiological state and contributes to the pathogenesis of arrhythmias in the diseased state. The cardiac neuraxis consists of multiple feedback loops consisting of efferent and afferent limbs, mediating neurotransmission to and from the heart. Efferent parasympathetic neurotransmission is mediated by the vagus nerve, while paravertebral sympathetic ganglia relay efferent sympathetic neurotransmission to the heart. The association between autonomic activity and ventricular arrhythmias (VAs) has been studied extensively in both experimental models and humans. Efferent parasympathetic activity is felt to be antiarrhythmic, while the activation of efferent sympathetic signals is proarrhythmic. The cardiac neuraxis undergoes remodeling and becomes dysfunctional in the setting of myocardial infarction (MI), chronic cardiomyopathy (CMY), and structural heat disease. Altered ANS function has been shown to initiate and/or maintain VAs via various mechanisms. Interventions targeting the ANS have been used clinically to treat VAs, particularly in patients with hereditary heart rhythm disorders and structurally abnormal hearts. Clinical applications of cardiac neuraxial modulation at the level of spinal cord, stellate ganglion, and peripheral sympathetic and vagus nerve are being developed. In this review, the anatomy of cardiac autonomic innervation, the association between autonomic activity and ventricular arrhythmogenesis, and clinical applications of neuraxial modulation in the treatment of VAs are discussed.

Mechanistic Insights into Sympathetic Neuronal Regeneration: Multitracer Molecular Imaging of Catecholamine Handling After Cardiac Transplantation.

Post-transplant reinnervation is a unique model to study sympathetic neuronal regeneration in vivo. The differential role of subcellular mechanisms of catecholamine handling in nerve terminals has not been investigated. Three different carbon-11-labeled catecholamines were used for positron emission tomography of transport (C-11 m-hydroxyephedrine, HED), vesicular storage (C-11 epinephrine, EPI), and metabolic degradation (C-11 phenylephrine). A 2-day protocol was used, including quantification of myocardial blood flow by N-13 ammonia. Resting myocardial blood flow and EPI, HED and phenylephrine retention were homogeneous in healthy volunteers (n=7). Washout was only observed for phenylephrine (T(1/2) 49±6 min). In nonrejecting, otherwise healthy heart transplant recipients (>1 year after surgery, n=10), resting myocardial blood flow was also homogenous. Regional catecholamine uptake of varying degrees was observed in the anterior left ventricular wall and septum. Overall, 24±19% of left ventricle showed HED uptake levels comparable with healthy volunteers, whereas it was only 8±7% for EPI (P=0.004 versus HED). Phenylephrine washout was not different from healthy volunteers in the area with restored EPI and HED retention (T(1/2) 41±7 min; P>0.05), but was significantly enhanced in the EPI/HED mismatch area (T(1/2) 36±8 min; P=0.008), consistent with inefficient vesicular storage and enhanced metabolic degradation. Regeneration of subcellular components of sympathetic nerve terminal function does not occur simultaneously. In the reinnervating transplanted heart, a region with normal catecholamine transport and vesicular storage is surrounded by a borderzone, where transport is already restored but vesicular storage remains inefficient, suggesting that vesicular storage is a more delicate mechanism. This observation may have implications for other pathologies involving cardiac autonomic innervation.

Analysis of Heart Rate Variability and Cardiac Autonomic Nerve Remodeling in Streptozotocin-induced Diabetic Rats.

Diabetes mellitus (DM) is associated with both cardiovascular and autonomic nervous system dysfunction. Spectral analysis of heart rate variability (HRV) can be used to monitor changes in response to autonomic innervation and stimulation of the heart. In this study, conducted in a rat model of diabetes, HRV and changes in associated neurotransmitters and neurotrophic factors in the right atrium (RA) were monitored. Diabetes was induced by streptozotocin (STZ) (60 mg/kg) in male Wistar rats, and HRV data were collected for 10 weeks by telemetry. Time and frequency domains of HRV data were analyzed using established metrics. The levels of various neural enzymes in the RA were determined by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence to characterize autonomic nerve remodeling. Insulin and methycobal were used to block the effects of STZ. HRV parameters reflecting parasympathetic tone (SDNN, RMSSD and HF domains) sharply decreased in the first 3 weeks after STZ administration; measures of sympathetic tone (SDANN) increased. After a series of adjustments, cardiac autonomic nerve innervation reached a new equilibrium, with a dominance of sympathetic tone. RA levels of tyrosine hydroxylase (TH) increased, and choline acetyltransferase (ChAT) decreased, indicating autonomic nerve remodeling. Levels of growth associated protein-43 (GAP43) and nerve growth factor (NGF) increased during the period of diabetes-induced cardiac-nerve damage; however, the level of ciliary neurotrophic factor (CNTF) decreased. The physical condition and indexes of rats were normalized in different degree after administration of the insulin and methycobal, but not completely recovered. STZ-induced diabetes was associated with cardiac autonomic nerve dysfunction at both the organ and molecular levels. Parasympathetic nerves exhibited severe damage and/or weak recovery; remodeling of sympathetic nerves predominated during 10-weeks of STZ-induced diabetes.

Differential Effects from Pharmacological and Electrical Stimulation of Rabbit Cardiac Ganglia

Cardiac autonomic innervation is complex due to the presence of an independent network of intrinsic cardiac ganglia, which are capable of differentially modulating cardiac function. Cardiac effects from these ganglia are studied using pharmacological or electrical stimulation and this was investigated in the current study. Langendorff perfused NZW rabbit hearts (2.5‐3kg) were used and ganglionic effects from left and right neuronal complexes (RNC) studied. Nicotine was used for pharmacological activation (0.1mg/10ul) and compared to electrical stimulation (20‐50Hz, 500‐700uA). Heart rate (HR) and atrioventricular conduction (AVC) was measured during control, muscarinic (atropine, 0.1uM), beta‐receptor (metoprolol, 1.8uM) and nicotinic (hexamthonium, 0.5uM) receptor blockade. Nicotine elicited mixed HR responses i.e. bradycardia alone, tachycardia alone and/or a mixed brady/tachycardia at each site. At the LNC, there was a smaller bradycardia (147.9±5.0 ‐ 142.2±5.6 bpm) but larger tachycardia (208.1±6.8 bpm) vs. the RNC (146.1±4.5, 131.5±5.4 [brady], 191.3±8.0 [tachy] bpm). Nicotine elicited AVC prolongation and/or shortening at each site. AVC prolongation was largest at the RNC (122.4±3.2 ‐ 129.5±3.6 ms) vs. the LNC (122.9±4.1 ‐ 126.2±4.3 ms). AVC shortening was indifferent. Only bradycardia and AVC prolongation was elicited by electrical stimulation. Responses were largest at the RNC. Bradycardia/AVC prolongation was blocked by atropine. Tachycardia/AVC shortening was blocked by metoprolol. Hexamthonium blocked all responses. These are the first data to show functional effects from ganglionic plexus stimulation in the rabbit with different responses from pharmacological vs. electrical stimulation.

Autonomic cardiac nerves: literature review.

The aim of this paper was to summarise the knowledge about the autonomic cardiac innervation. It is generally known, that the cardiac nervous system consists of nerve plexoganglionic structures located mostly around the strategic regions of the heart. They consist of two main types of components: parasympathetic neurons, which exert an inhibitory effect, and sympathetic postganglionic nerve fibres, which stimulate the cardiac conduction system, and myocardial cells. However, many authors describe that cardiac ganglia contain various populations of neurons. The largest group are classical cholinergic neurons. The second group of cardiac neurons are cells of dual, cholinergic-adrenergic character. There is also subpopulation of small intensely fluoroscent cells of typically adrenergic phenotype. Moreover, many authors indicated the presence of various neurotransmitters in various combinations. In this way, the neurons in cardiac ganglia are a neurochemical complex beyond the classical vision of parasympathetic ganglia.

[Ischemic cardiomyopathy. Parameters of the autonomic tone].

Despite significant improvements with respect to medical and interventional therapies, late mortality after myocardial infarction remains high. Therefore, the identification of high-risk patients who benefit from an intensified treatment approach is of great clinical interest. Experimental and clinical studies have shown that dysfunction of the cardiac autonomic innervation is associated with a poor prognosis in patients with ischemic cardiomyopathy. Clinical routine allows for noninvasive assessment of the cardiac autonomic innervation by means of ECG analysis. Parameters of heart rate variability reflect sympathetic and parasympathetic regulatory processes at the sinus node level. Recently, low frequency oscillatory modulations of the T-wave, which reflect sympathetic effects at the level of ventricular myocardium, have been identified. To optimize risk assessment, different parameters of the autonomic function can be combined. A large number of studies have proven the prognostic value of parameters of the autonomic nervous system. However, randomized controlled trials are needed to show whether patients with ischemic cardiomyopathy and autonomic dysfunction benefit from specific therapeutic interventions, i.e., intensified monitoring or ICD implantation.