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.