The Intrinsic Cardiac Nervous System and Its Role in Cardiac Pacemaking and Conduction

Figure 1. Model of the hierarchical control of the heart by the cardiac autonomic nervous system (CANS). The intrinsic cardiac nervous system (ICNS) contains efferent (parasympathetic and sympathetic) neurons, local afferent neurons and local circuit neurons. The intrathoracic extracardiac ganglia (stellate ganglia and middle cervical ganglia) contain sympathetic neurons, local afferent and local circuit neurons. The intrathoracic ganglia (intra- and extracardiac) work in close coordination as a nested loop, which is further tuned by the CNS (spinal cord, brainstem, hypothalamus, and forebrain) resulting in the regulation of cardiac function on a beat-to-beat basis. DRG: dorsal root ganglion; β1AR: beta 1 adrenergic receptor, M2: muscarinic acetylcholine receptor type 2. Neurite: local afferent neurites embedded in the cardiac walls. Figure adapted from Ardell & Armour J. Phys published by Wiley 2016 [2].

Figure 2. (A) Regionalization of the neural crest along the dorsal neural tube of the mouse embryo (E10.5): cranial (purple), vagal (green), trunk (orange), and sacral (yellow). Vagal neural crest cells (NCCs) are further subdivided into: cardiac (red) and enteric (blue) lineages. (B) Migration of cardiac NCCs through or lateral to the somites into the branchial arch arteries and further into the outflow tract. (C) Transcriptional network involved in the specification and differentiation of NCCs into sympathetic and parasympathetic neurons. White box: factors involved in both pathways; blue: factors involved in the differentiation of sympathetic neurons and red: of parasympathetic neurons. Abbreviations: BMPs- bone morphogenic proteins; ChAT- choline acetyltransferase; DBH- dopamine β-hydroxylase; GATA3- GATA binding protein 3; HAND2: heart and neural crest derivative expressed 2; MASH1- mammalian achaete-scute homologue; PHOX2 (A or B)- paired-like homeobox 2A or 2B; TH- tyrosine hydroxylase; vAChT- vesicular acetylcholine transporter. (A) reproduced with permission from Hutchins, E.J., et al. Dev. Biol published by Elsevier 2018 [29]; (B) reproduced with permission from Végh A.M.D., et…

Figure 3. Intracardiac innervation of the zebrafish, rat and mouse hearts. (A) Whole mount immunostaining using antibodies directed against acetylated tubulin (AcT) and human neuronal protein (Hu) to label the ICNS of the zebrafish heart. (B) Schematic overview of the major elements of cardiac innervation. Boxed areas: sinoatrial plexus (SAP) and atrioventricular plexus (AVP). Abbreviations for A and B: A—atrium; AVP—atrioventricular plexus; BA—bulbus arteriosus; DC—ducts of Cuvier; LX and RX, left and right vagosympathetic trunks; SAP- sinoatrial plexus; SV—sinus venosus; V—ventricle; VA—ventral aorta (to the gills). (C) Posterior view of a 3D reconstructed male rat heart showing the context, extent, and distribution of the intrinsic cardiac neurons (yellow labelled), located on superior and posterior surfaces of the atria (D) Schematic overview of the intracardiac ganglia in the mouse heart, dorsal view. Dotted lines delineate the heart hilum, polygonal areas the main locations of the cardiac ganglia. Abbreviations for C and D: Ao- aorta; CS- coronary sinus veins; CV—caudal vein; DRA—dorsal right atrial; IAS—interatrial septum; LA—left atrium; LAA (or LAu)—left auricle; LCV—left cranial;…

Figure 4. Neurocardiac transmission in the sinoatrial node (SAN). (A) Diagram illustrating the distinct cell types of the intracardiac ganglia and their putative roles: SAH (slow afterhyperpolarization) cells are the principal cells and the only ones receiving pre-ganglionic inputs. S (somatic) cells and some SAH cells can receive inputs from P (pacemaker) cells. P cells are putative sensory neurons. (B) Electron micrograph of the neurocardiac junction at the level of the sinus venosus of the toad. Cholinergic (C) and adrenergic (A) varicosities in contact with a cardiomyocyte (M). No membrane specializations are visible except for an electron dense area as indicated by the arrows. (C) Reconstruction of the neurocardiac junction depicted in (B). Cholinergic vesicles are present in the prejunctional membrane facing the cardiomyocyte and the adrenergic varicosity, respectively whilst adrenergic vesicles are mainly present in close opposition to the cardiomyocyte. The black area between the neuronal varicosity and the cardiomyocyte represents the cleft. Panel (A) reproduced with permission from Jänig, W., J. Physiol. published by Wiley, 2011 [91]. Panel (B,C) reproduced with permission from…

Figure 5. Diagram illustrating the crosstalk by the sympathetic and parasympathetic varicosities at the level of a sinoatrial node myocyte. The parasympathetic neuron can release acetylcholine, nitric oxide and vasoactive intestinal peptide, whilst the sympathetic neuron norepinephrine, ATP and neuropeptide Y. This figure was created using images from Servier Medical Art Commons Attribution 3.0 Unported License (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.