The intrinsic cardiac nervous system
The intrinsic cardiac nervous system comprises efferent parasympathetic and sympathetic neurons, afferent (sensory) neurons, and local circuit neurons/interneurons acting via diverse neurotransmitters (Figure 1) (19-24). For many years, studies on the mammalian heart mostly focused on determining the location of epicardial ganglia using histologic examination of heart sections, resulting in the concept of ganglionated plexuses (GPs) consisting of grouping ganglia in different sites (3, 4, 25). However, this somewhat simplistic notion has been challenged by recent observations that epicardial ganglia may be very widely distributed, and their sizes may be extremely variable ranging from those that are only observable with a microscope to those that are easily discernible with the naked eye (26). Furthermore, the hearts of humans and some mammalian species contain more than one and a half thousand ganglia (4, 26, 27). Thus, the actual number and distribution of these ganglia might only be identified on the non-sectioned heart preparations (26). By staining of intrinsic cardiac neural plexus on the whole heart, it has been disclosed that the heart is under neuronal control through one intrinsic epicardiac neural plexus, nerves of which extend to distinct cardiac regions by seven neural pathways or routes, called as epicardiac neural ganglionated subplexi (sGPs) (26-29) (Figure 2). Anatomically, nerves accessing the heart penetrate through the heart hilum at the base of the heart into the epicardium and to the intrinsic ganglia distributed mostly within the epicardium. Then, the postganglionated intrinsic nerves extend towards the specific atrial or ventricular regions - around the sinoatrial node, the roots of caval and pulmonary veins (PVs), and near the atrioventricular node (Figures 1 and 2). The main difference of GP nomenclature from that of sGP terminology is that specific GPs are parts of the larger ganglionated fields of specific sGPs. Since epicardial ganglia are persistently distributed along those sGP nerves, the use of the inclusive term ‘ganglia’ instead of GPs and sGPs might be more reasonable to define those areas anatomically. Because electrophysiological detection and ablation ofventricular sGPs has been practically unexamined so far, the following part of the review will discuss the intrinsic ganglia distributed in the atrial epicardium.
The organization of the intrinsic cardiac autonomic nervous system in non-human mammals
A significantly lower number of nerve cell bodies is evident in structure of sGPs of smaller mammals as compared to larger ones (24-34). Also, while in small mammals, ganglionic cells are usually clustered across the hilum, they are distributed more widely across both atria in larger mammals. Essentially, five atrial sGPs have been defined in non-human mammals (Figure 2): 1) the left dorsal sGP (LDsGP); 2) the middle dorsal sGP (MDsGP); 3) the ventral left atrial sGP (VLAsGP); 4) the ventral right atrial sGP (VRAsGP); and 5) the dorsal right atrial sGP (DRAsGP) (28-31).
The organization of the intrinsic cardiac autonomic nervous system in humans
Although, in general, the morphology of the human sGPs corresponds with that in larger mammals, particularly, with the canines, topographical and quantitative inter-species differences are evident (26, 28, 30, 33, 34). According to GP nomenclature by Armour et al (4) that is commonly used to define the distribution of intrinsic cardiac ganglia in experimental and clinical studies, the following five major and one minor atrial locations are consistently identified in humans: 1)the superior right atrial GP located on the postero-superior surface of the right atrium (RA) adjacent to the junction of the SVC and the RA; 2) the superior left atrial GP on the postero-superior surface of the left atrium (LA) between the PVs; 3) the posterior right atrial GP located adjacent to the interatrial groove; 4)the posteromedial left atrial GP on the postero-medial surface of the LA; 5) the interatrial septal GP consisting of fusion and extensions of the posterior right atrial GP and the posteromedial left atrial GP ; and 6) the posterolateral left atrial GP is identified on the postero-lateral surface of the LA. According to Pauza et al (28, 35, 36, 68) who studied the intrinsic nerves and ganglia on the human whole-mount heart preparations, these 5 GPs are densely interconnected by thinner nerves and, therefore should be considered as just distinctive, ganglionated areas of the continuous cardiac ganglionated nerve plexus (Figure 2, Table 1). Since these ganglionated areas have their specific neural fibers accessing through cardiac hilum nerves as well as the nerves that extend from these ganglia towards the specific atrial and ventricular regions, they were referred to by Pauza et al (28) as sGPs. On the human atria, there are discerned (1) the VRA (anterior right) sGP which occupies ventral superior right atrial region, ventral side of the root of the SVC, and ventral inferior right atrial region; 2) the VLA (anterior left) sGP covers the rather narrow ventral superior left atrial region; 3)the LD (posterior left) sGP distributes across the left coronary sulcus, region of dorsal left coronary sulcus, and middle left atrial region regions and contains abundant ganglia; 4) the MD (posterior middle) sGP extends on the dorsal superior left atrial region and around the crux cordis; and 5) the DRA (posterior right) sGPwhich resides in the dorsal superior right atrial region, dorsal side of the root of the SVC, and region over the interatrial septum. Innervation routes of these atrial sGPs are provided in Online Supplemental File.
The ligament of Marshall (LOM) or neural fold of the LA is considered part of the intrinsic cardiac ANS. Immunohistochemistry confirmed that it involves a number of branches of the left vagus, specifically the LDsGP , and sympathetic nerve fibers (37). Cholinergic nerve fibers originating in the LOM were found to innervate surrounding left atrial structures, including the PVs, left atrial auricle or appendage, and coronary sinus (Figure 3). It becomes the vein of Marshall caudally as it connects with the coronary sinus.