Part and Parcel of the Cardiac Autonomic Nerve System: Unravelling Its Cellular Building Blocks during Development (original) (raw)
Related papers
Journal of Anatomy, 1999
This study was prompted by the prospect of transgenic pigs providing donor hearts for transplantation in human recipients. Autonomic innervation is important for the control of cardiac dynamics, especially in the conduction system. Our objective was to assess the relative distribution of autonomic nerves in the pig heart, focusing initially on the conduction system but addressing also the myocardium, endocardium and epicardium (see . Quantitative immunohistochemical and histochemical techniques were adopted. All regions of the conduction system possessed a significantly higher relative density of the total neural population immunoreactive for the general neuronal marker protein gene product 9.5 (PGP 9.5) than did the adjacent myocardium. A similar density of PGP 9.5-immunoreactive innervation was observed between the sinus node, the transitional region of the atrioventricular node, and the penetrating atrioventricular bundle. A differential pattern of PGP 9.5-immunoreactive innervation was present within the atrioventricular node and between the components of the ventricular conduction tissues, the latter being formed by an intricate network of Purkinje fibres. Numerous ganglion cell bodies were present in the peripheral regions of the sinus node, in the tissues of the atrioventricular groove, and even in the interstices of the compact atrioventricular node. Acetylcholinesterase (AChE)-containing nerves were the dominant subpopulation observed, representing 60-70 % of the total pattern of innervation in the nodal tissues and penetrating atrioventricular bundle. Tyrosine hydroxylase (TH)-immunoreactive nerves were the next most abundant neural subpopulation, representing 37 % of the total pattern of innervation in the compact atrioventricular node compared with 25 % in the transitional nodal region. A minor population of ganglion cell bodies within the atrioventricular nodal region displayed TH immunoreactivity. The dominant peptidergic nerve supply possessed immunoreactivity for neuropeptide Y (NPY), which displayed a similar pattern of distribution to that of TH-immunoreactive nerve fibres. Calcitonin gene-related peptide (CGRP)immunoreactive nerves represented 8-9 % of the total innervation of the nodal tissues and penetrating atrioventricular bundle, increasing to 14-19 % in the bundle branches. Somatostatin-immunoreactive nerve fibres were relatively sparse (4-13 % of total innervation) and were most abundant in the nodes, especially the compact atrioventricular node. The total pattern of innervation of the porcine conduction system was relatively homogeneous. A substantial proportion of nerve fibres innervating the nodal tissues could be traced to intracardiac ganglia indicative of an extensive intrinsic supply. The innervation of the atrioventricular node and ventricular conduction tissues was similar to that observed in the bovine heart, but markedly different to that of the human heart. It is important that we are aware of these findings in view of the future use of transgenic pig hearts in human xenotransplantation.
Localisation and quantitation of autonomic innervation in the porcine heart I: conduction system
Journal of Anatomy, 1999
This study was prompted by the prospect of transgenic pigs providing donor hearts for transplantation in human recipients. Autonomic innervation is important for the control of cardiac dynamics, especially in the conduction system. Our objective was to assess the relative distribution of autonomic nerves in the pig heart, focusing initially on the conduction system but addressing also the myocardium, endocardium and epicardium (see . Quantitative immunohistochemical and histochemical techniques were adopted. All regions of the conduction system possessed a significantly higher relative density of the total neural population immunoreactive for the general neuronal marker protein gene product 9.5 (PGP 9.5) than did the adjacent myocardium. A similar density of PGP 9.5-immunoreactive innervation was observed between the sinus node, the transitional region of the atrioventricular node, and the penetrating atrioventricular bundle. A differential pattern of PGP 9.5-immunoreactive innervation was present within the atrioventricular node and between the components of the ventricular conduction tissues, the latter being formed by an intricate network of Purkinje fibres. Numerous ganglion cell bodies were present in the peripheral regions of the sinus node, in the tissues of the atrioventricular groove, and even in the interstices of the compact atrioventricular node. Acetylcholinesterase (AChE)-containing nerves were the dominant subpopulation observed, representing 60-70 % of the total pattern of innervation in the nodal tissues and penetrating atrioventricular bundle. Tyrosine hydroxylase (TH)-immunoreactive nerves were the next most abundant neural subpopulation, representing 37 % of the total pattern of innervation in the compact atrioventricular node compared with 25 % in the transitional nodal region. A minor population of ganglion cell bodies within the atrioventricular nodal region displayed TH immunoreactivity. The dominant peptidergic nerve supply possessed immunoreactivity for neuropeptide Y (NPY), which displayed a similar pattern of distribution to that of TH-immunoreactive nerve fibres. Calcitonin gene-related peptide (CGRP)immunoreactive nerves represented 8-9 % of the total innervation of the nodal tissues and penetrating atrioventricular bundle, increasing to 14-19 % in the bundle branches. Somatostatin-immunoreactive nerve fibres were relatively sparse (4-13 % of total innervation) and were most abundant in the nodes, especially the compact atrioventricular node. The total pattern of innervation of the porcine conduction system was relatively homogeneous. A substantial proportion of nerve fibres innervating the nodal tissues could be traced to intracardiac ganglia indicative of an extensive intrinsic supply. The innervation of the atrioventricular node and ventricular conduction tissues was similar to that observed in the bovine heart, but markedly different to that of the human heart. It is important that we are aware of these findings in view of the future use of transgenic pig hearts in human xenotransplantation.
Cardiac Innervation and the Autonomic Nervous System in Sudden Cardiac Death
Cardiac electrophysiology clinics, 2017
Neural remodeling in the autonomic nervous system contributes to sudden cardiac death. The fabric of cardiac excitability and propagation is controlled by autonomic innervation. Heart disease predisposes to malignant ventricular arrhythmias by causing neural remodeling at the level of the myocardium, the intrinsic cardiac ganglia, extracardiac intrathoracic sympathetic ganglia, extrathoracic ganglia, spinal cord, and the brainstem, as well as the higher centers and the cortex. Therapeutic strategies at each of these levels aim to restore the balance between the sympathetic and parasympathetic branches. Understanding this complex neural network will provide important therapeutic insights into the treatment of sudden cardiac death.
Initiation of the cardiac cycle is myogenic, originating in the sinuatrial node (SA). It is harmonizied in rate, force and output by autonomic nerves which operate on the nodal tissues and their prolongations, on coronary vessels and on the working atrial and ventricular musculature. All the cardiac branches of the N.vagus, X. cranial nerve, (parasympathetic) and all the sympathetic branches (except the cardiac branch of the superior cervical sympathetic ganglion) contain both afferent and efferent fibres; the cardiac branch of the superior cervical sympathetic ganglion is entirely efferent. Sympathetic fibres accelerate the heart and dilate the coronary arteries when stimulated, whereas parasympathetic (vagal) fibres slow the heart and cause constriction of coronary arteries. Preganglionic cardiac SY (sympathetic) axons arise from neurones in the intermediolateral column of the upper four or five thoratic spinal segments. Some synapse in the corresponding upper thoratic SY ganglia, others ascend to synapse in the cervical ganglia; postganglionic fibres from these ganglia form the SY cardiac nerves (from ganglion cervicale sup. goes N.cardiacus cervicalis sup.; form ganglion cervicale med. Goes N.cardiacus cervicalis sup.; from ganglion cervicothoracicum(stellatum) goes N.cardiacus cervicalis inf.; from ganglion thoracicum I-IV go Nn.cardiaci thoracici). Preganglionaric cardiac PSY (parasympathetic) axons arise from neurones in either the dorsal vagal nucleus ambiguus; they run in vagal cardiac branches to synapse in the cardiac plexuses and atrial walls. In man (like in most mammals) intrinsic cardiac neurones are limited to the atria and interatrial septum, and are most numerous in the subepicarial connective tissue near the SA and AV nodes.
Heart Autonomic Nervous System: Basic Science and Clinical Implications
Autonomic Nervous System [Working Title], 2022
The heart has an intrinsic conduction system that consists of specialized cells. The heart receives extensive innervation by both sympathetic and parasympathetic systems of the ANS. The ANS influences most heart functions by affecting the SA node, AV node, myocardium, and small and large vessel walls. The sympathetic system carries an excitatory effect on heart functions. Conversely, the parasympathetic system has inhibitory effects on heart functions. ANS abnormalities in terms of anatomy and physiology can cause various heart abnormalities. ANS abnormalities associated with electrical abnormalities can cause a variety of heart manifestations. Besides electrical abnormalities, ANS also correlates with ischemic heart disease. Following electrical and ischemic instability, ANS also have direct effect on action potential duration restitution. By understanding the mechanism of influence of the anatomy and physiology of the ANS heart and its influence on various heart abnormalities, we ...
Innervation of the rabbit cardiac ventricles
The rabbit is widely used in experimental cardiac physiology, but the neuroanatomy of the rabbit heart remains insufficiently examined. This study aimed to ascertain the architecture of the intrinsic nerve plexus in the walls and septum of rabbit cardiac ventricles. In 51 rabbit hearts, a combined approach involving: (i) histochemical acetylcholinesterase staining of intrinsic neural structures in total cardiac ventricles; (ii) immunofluorescent labelling of intrinsic nerves, nerve fibres (NFs) and neuronal somata (NS); and (iii) transmission electron microscopy of intrinsic ventricular nerves and NFs was used. Mediastinal nerves access the ventral and lateral surfaces of both ventricles at a restricted site between the root of the ascending aorta and the pulmonary trunk. The dorsal surface of both ventricles is supplied by several epicardial nerves extending from the left dorsal ganglionated nerve subplexus on the dorsal left atrium. Ventral accessing nerves are thicker and more numerous than dorsal nerves. Intrinsic ventricular NS are rare on the conus arteriosus and the root of the pulmonary trunk. The number of ventricular NS ranged from 11 to 220 per heart. Four chemical phenotypes of NS within ventricular ganglia were identified, i.e. ganglionic cells positive for choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), and biphenotypic, i.e. positive for both ChAT/ nNOS and for ChAT/tyrosine hydroxylase. Clusters of small intensely fluorescent cells are distributed within or close to ganglia on the root of the pulmonary trunk, but not on the conus arteriosus. The largest and most numerous intrinsic nerves proceed within the epicardium. Scarce nerves were found near myocardial blood vessels, but the myocardium contained only a scarce meshwork of NFs. In the endocardium, large numbers of thin nerves and NFs proceed along the bundle of His and both its branches up to the apex of the ventricles. The endocardial meshwork of fine NFs was approximately eight times denser than the myocardial meshwork. Adrenergic NFs predominate considerably in all layers of the ventricular walls and septum, whereas NFs of other neurochemical phenotypes were in the minority and their amount differed between the epicardium, myocardium and endocardium. The densities of NFs positive for nNOS and ChAT were similar in the epicardium and endocardium, but NFs positive for nNOS in the myocardium were eight times more abundant than NFs positive for ChAT. Potentially sensory NFs positive for both calcitonin gene-related peptide and substance P were sparse in the myocardial layer, but numerous in epicardial nerves and particularly abundant within the endocardium. Electron microscopic observations demonstrate that intrinsic ventricular nerves have a distinctive morphology, which may be attributed to remodelling of the peripheral nerves after their access into the ventricular wall. In conclusion, the rabbit ventricles display complex structural organization of intrinsic ventricular nerves, NFs and ganglionic cells. The results provide a basic anatomical background for further functional analysis of the intrinsic nervous system in the cardiac ventricles.
The development of the sympathetic system of the heart
2018
Development of the sympathetic nervous system begins at about embryonic day 9 in mice with the migration of the neural crest cells to the dorsal aorta and the development of neurons and the sympathetic ganglia. This is followed by the axonal elongation towards the developing cardiac tissue. This process is directed by a series of signal ligands including ephrin-B1, semaphorin 3a (Sema3a), F-Spondin, bone morphogenetic proteins (BMPs), Wnt-1 protein, neurotrophin-3 (NT-3), nerve growth factor (NGF) and artemin (ARTN). Once at the developing heart, the nerve fibres follow the coronary veins in the subepicardium using NGF and the chemorepellent Sema3a as signals. Here they interact with the cardiac conduction system. Although these cardiac neural cells are part of the autonomic system, they are developed later, mainly on the epicardial surface. Bilateral innervation of the heart comes from the middle cervical stellate (MC-S) ganglion. Although the left ventricle and atrium receive nora...
Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death
Cardiovascular Research, 2001
The purpose of this article is to review the nerve sprouting hypothesis of sudden cardiac death. It is known that sympathetic stimulation is important in the generation of sudden cardiac death. For example, there is a diurnal variation of sudden death rate in patients with myocardial infarction. Beta blockers, or drugs with beta blocking effects, are known to prevent sudden cardiac death. It was unclear if the cardiac nerves in the heart play only a passive role in the mechanisms of sudden death. To determine if nerve sprouting and neural remodeling occur after myocardial infarction, we performed immunocytochemical studies of cardiac nerves in explanted native hearts of transplant recipients. We found that there was a positive correlation between nerve density and a clinical history of ventricular arrhythmia. Encouraged by these results, we performed a study in dogs to determine whether or not nerve growth factor (NGF) infusion to the left stellate ganglion can facilitate the development of ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD). The results showed that augmented myocardial sympathetic nerve sprouting through NGF infusion plus atrioventricular (AV) block and MI result in a 44% incidence (four of nine dogs) of SCD and a high incidence of VT in the chronic phase of MI. In contrast, none of the six dogs (with AV block and MI) without NGF infusion died suddenly or had frequent VT episodes. Based on these findings, we propose the nerve sprouting hypothesis of ventricular arrhythmia and SCD. The hypothesis states that MI results in nerve injury, followed by sympathetic nerve sprouting and regional (heterogeneous) myocardial hyperinnervation. The coupling between augmented sympathetic nerve sprouting with electrically remodeled myocardium results in VT, VF and SCD. Modification of nerve sprouting after MI may provide a novel opportunity for arrhythmia control.
Defining Cardiac Nerve Architecture During Development, Disease, and Regeneration
ABSTRACTCardiac nerves regulate neonatal mouse heart regeneration and are susceptible to pathological remodeling following adult injury. Understanding cardiac nerve remodeling can lead to new strategies to promote cardiac repair. Our current understanding of cardiac nerve architecture has been limited to two-dimensional analysis. Here, we use genetic models, whole-mount imaging, and three-dimensional modeling tools to define cardiac nerve architecture and neurovascular association during development, disease, and regeneration. Our results demonstrate that cardiac nerves sequentially associate with coronary veins and arteries during development. Remarkably, our results reveal that parasympathetic nerves densely innervate the ventricles. Furthermore, parasympathetic and sympathetic nerves develop synchronously and are intertwined throughout the ventricles. Importantly, the regenerating myocardium reestablishes physiological innervation, in stark contrast to the non-regenerating heart....
Role of the Autonomic Nervous System in Modulating Cardiac Arrhythmias
Circulation Research, 2014
The autonomic nervous system plays an important role in the modulation of cardiac electrophysiology and arrhythmogenesis. Decades of research has contributed to a better understanding of the anatomy and physiology of cardiac autonomic nervous system and provided evidence supporting the relationship of autonomic tone to clinically significant arrhythmias. The mechanisms by which autonomic activation is arrhythmogenic or antiarrhythmic are complex and different for specific arrhythmias. In atrial fibrillation, simultaneous sympathetic and parasympathetic activations are the most common trigger. In contrast, in ventricular fibrillation in the setting of cardiac ischemia, sympathetic activation is proarrhythmic, whereas parasympathetic activation is antiarrhythmic. In inherited arrhythmia syndromes, sympathetic stimulation precipitates ventricular tachyarrhythmias and sudden cardiac death except in Brugada and J-wave syndromes where it can prevent them. The identification of specific au...