Anatomy of the cardiac nervous system with clinical and comparative morphological implications
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- Kawashima, T. Anat Sci Int (2011) 86: 30. doi:10.1007/s12565-010-0096-0
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Unlike autonomic nervous preservation in other surgeries for improving patient quality of life, autonomic cardiac nervous system (ACNS) preservation has been neglected in cardiovascular surgery because of technical difficulties and other unsolved issues. Because such ACNS preservation in cardiovascular surgery is anticipated in the future, detailed anatomical investigation of the human ACNS is required. Therefore, we have conducted morphological studies of the ACNS from macroscopic, clinical, and evolutionary anatomical viewpoints. In this study, I review detailed anatomical studies of the human ACNS together with their clinical implications. In addition, the evolutionary comparative anatomical significance of primate ACNS is also summarized to help understand and translate the findings of functional experiments to humans. These integrated findings will be the subject of a future study unifying molecular embryological and anatomical findings to clarify cardiac functions based on functional animal experiments, clinical applications such as improving surgery techniques and individual order-made surgery in cardiac surgery, and for future evaluation in regenerative medicine.
KeywordsAutonomic cardiac nervous systemClinical anatomyComparative anatomyEvolutionPrimateHuman heartCardiac nerveCardiac branch
Superior interventricular artery (anterior interventricular/descending branch of the coronary artery)
Accessory middle cervical ganglion
Anterior cardiac vein
Circumflex branch of the coronary artery
Common carotid artery
Cervicothoracic (stellate) ganglion
First to eighth cervical nerves
Great cardiac vein
Inferior (vagal) cardiac branch
Inferior cervical ganglion
Inferior cervical cardiac nerve
Inferior caval vein
Nerve branches to the lung
Left common carotid artery
Left coronary artery
Left subclavian artery
Left superior vena cava
Middle cervical ganglion
Middle cardiac nerve
Oblique vein of the left atrium
Inferior pulmonary vein
Superior pulmonary vein
Right common carotid artery
Right coronary artery
Retroesophageal right subclavian artery
Recurrent laryngeal nerve of the vagus nerve
Right subclavian artery
Right superior vena cava
Sinuatrial nodal branch of the coronary artery
Superior (vagal) cardiac branch
Nerve to the subclavian muscle
Superior cervical ganglion
Superior cardiac nerve
Superior caval vein
Thoracic (vagal) cardiac branch
Thoracic cardiac nerve
First to sixth thoracic nerves
Second to sixth thoracic ganglia
Because the autonomic cardiac nervous system (ACNS) controls life-maintaining functions such as pulse, blood pressure, blood flow and cardiac pain delivery, many gross and clinical anatomical studies of the ACNS have been conducted over the long course of medical history. However, most of the anatomical research on ACNS has been incomplete because of the long course from the origin to the target and the existence of two systems, i.e., sympathetic and parasympathetic. Thus, most gross anatomical studies on the ACNS have been limited to either the sympathetic or parasympathetic nervous system. Furthermore, studies on the sympathetic nervous system have been divided into the following two types: research on the proximal part from the spinal nerves to the sympathetic ganglia (Axford 1927–1928; Becker and Grunt 1957; Harman 1900; Hoffman 1957; Jamieson et al. 1952; Kuntz 1946; Mitchell 1953; Pick and Sheehan 1946; White and Smithwick 1952; Wrete 1959), and research on the distal part from the sympathetic ganglia to the visceral nerves (Ellison and Williams 1962; Fukuyama 1982; Hausman 1956; Janes et al. 1986; Kuntz and Morehouse 1930; Mizeres 1963; Mitchell 1953; Pick 1970). Although a few excellent anatomical studies on the ACNS have been conducted recently (Batulevicius et al. 2003, 2005; Pauza et al. 2000, 2002; Saburkina et al. 2010; Tanaka et al. 1998, 2007), numerous points remain to be clarified regarding future human applications.
Because accurate anatomical knowledge of autonomic innervation is essential for function-preserving operations aimed at improving patient quality of life (QOL), anatomical reexamination of the autonomic nervous system in the abdominal and pelvic regions has been performed. In cardiovascular surgery, however, operations to preserve the autonomic nervous system have never been performed because of technical difficulties and other unsolved issues. Furthermore, autonomic regeneration may help to accelerate nonpreserving operation of ACNS in complicated cardiac surgery. However, it is well known that patients cannot perceive anginal pain caused by denervation after undergoing cardiac transplantation (Raczak et al. 1999; Bengel et al. 2001, 2002). In addition, denervated patients constantly experience orthostatic hypotension and ineffectiveness of antiarrhythmic agents such as atropine and foxgloves, which act on autonomic nerves. Because this type of cardiovascular surgery is anticipated in the future, detailed anatomical investigation of the human ACNS is necessary.
To date, several mammals, such as rats, mice, and dogs, have been used as model animals for medical and developmental studies of the ACNS to understand its function and morphogenesis. The morphology of the ACNS in these experimental animals shows considerable interspecific differences in line with those shown in the evolutionary divergence timeline. In addition, to completely understand the morphological principles of the ACNS, it is essential to examine the ACNS in primates—positioned phyletically between humans and rodents—with regard to whether ACNS morphology reflects its phylogeny.
In this review, I discuss the detailed human ACNS anatomy, the clinical significance of topographical changes in branchial arterial anomalies of the ACNS, and the evolutionary morphology of the primate ACNS based on previous studies by our group and others.
Anatomy of human cardiac innervation and its clinical significance
Because many technical terms regarding ACNS anatomy have been introduced arbitrarily without clear definitions, several authors have separately coined new terms, leading to great difficulties in comparing results among previous studies (Nonidez 1939; Mitchell 1953; Hoffman 1957; Pick 1970; Fukuyama 1982; Tanaka et al. 1998). Our definitions of the cardiac nerve/branch follow those coined by Fukuyama (1982), with modifications. The cardiac nerves connecting to the cardiac plexus or distributing to the heart are named according to their origins as follows. Superior cardiac nerve (SN) is the cardiac nerve originating from the superior cervical ganglion (SG) or sympathetic trunk (ST) between SG and middle cervical ganglion (MG); middle cardiac nerve (MN) is the cardiac nerve originating from MG, vertebral ganglion (VG), or ST between MG and inferior cervical ganglion (IG) (or the cervicothoracic ganglion, CT), including the subclavian ansa; inferior cardiac nerve (IN) is the cardiac nerve originating from IG or CT; thoracic cardiac nerve (TN) is the cardiac nerve originating from the thoracic ganglia (TG) or the thoracic ST below IG or CT. Furthermore, each cardiac branch is named according to its origin as follows. Superior cardiac branch (SB) is the cardiac branch originating from the vagus nerve proximal to the branching site of the recurrent laryngeal nerve (RL); inferior cardiac branch (IB) is the cardiac branch originating from any part of the RL; thoracic cardiac branch (TB) is the cardiac branch originating from the vagus nerve distal to the branching site of the RL.
Furthermore, we use some modified terms for the human heart and its surrounding structures such as superior (anterior) and inferior (posterior) interventricular arteries and caval veins (vena cava), based on their correct orientations provided by Anderson et al. (2004) and Anderson and Loukas (2009). Most of the abbreviations used follow the accepted conventions, facilitating easy identification.
MG was observed on 33 sides (33/36 sides, 91.7%), and it communicated with C3 (11/33 sides, 33.3%), C4 (29/33 sides, 87.9%), C5 (20/33 sides, 60.6%), and C6 (5/33 sides, 15.2%).
VG was observed on 34 sides (34/36 sides, 94.7%), and it communicated with C4 (1/34 side, 2.9%), C5 (2/34 sides, 5.9%), C6 (3/34 sides, 8.8%), and C7 (6/34 sides, 17.6%).
A single IG without fusion to TG was present on five sides (5/36 sides, 13.9%), whereas most cases formed a CT (31/36 sides, 86.1%) and communicated with C5 (2/36, 5.6%), C6 (4/36, 11.1%), C7 (27/36, 75.0%), C8 (100.0%), T1 (100.0%), T2 (25/36, 69.4%), and T3 (1/36, 2.8%). The ganglion communicating with T3 was a CT comprising IG, 1TG, and 2TG (Fig. 1c).
Furthermore, these data on communication between the sympathetic ganglia and spinal nerves do not include the vertebral nerve (VN) consisting of the nerve following the vertebral artery and entering into the foramen transversarium. We observed VN originating from VG on 26/34 sides (76.5%) and IG or CT on 34/36 sides (94.4%). Based on further examination of VN after demineralization and removing the bony elements on six sides, VN communicated with C5 (3/6 sides, 50.0%), C6 (6/6 sides, 100.0%), and C7 (6/6 sides, 100.0%). Therefore, VN appears to be a complex of communicating branches to the spinal cervical nerve through the foramen transversarium and it was termed deep ST by Wrete (1959).
Although differences in frequencies of communicating branches between the sympathetic ganglia and spinal nerves appear to be due partially to ethnicity, most results have been consistent and are in agreement with previous reports (Axford 1927–1928; Becker and Grunt 1957; Harman 1900; Hoffman 1957; Jamieson et al. 1952; Kuntz 1946; Mitchell 1953; Pick and Sheehan 1946; White and Smithwick 1952; Wrete 1959). Only the appearances of MG and VG are controversial. Hoffman (1957) and Pick (1970) mentioned that these two ganglia were generally small and their ganglion cells could be observed throughout the ST between SG and IG, even if they could not be readily observed. Although this histological finding is important with regard to their morphological significance, it is also significant for clinicians that the frequency of VG is higher than that of MG and both the ganglia are not always macroscopically evident.
Our findings on origins and appearances of the sympathetic cardiac nerves and parasympathetic vagal cardiac nerves are as follows (Kawashima and Sasaki 2007; Fig. 2). SN originating from SG and ST was observed on 46/52 (88.5%) and 37/52 sides (71.2%), respectively. MN originating from MG, VG, and ST was observed on 43/49 (87.8%), 43/50 (86.0%), and 40/52 sides (76.9%), respectively. IN and TN were observed on 43/50 (86.0%) and 35/52 sides (67.3%), respectively. On the other hand, all parasympathetic vagal cardiac branches, which included SB, IB, and TB, were further consistently observed on 52/52 (100.0%), 52/52 (100.0%), and 43/52 sides (82.7%), respectively (Kawashima and Sasaki 2007).
Although opinions that MN originating from MG and VG, and all parasympathetic cardiac branches are main contributors, in the human ACNS are in agreement with ours (Mitchell 1953; Ellison and Williams 1962; Fukuyama 1982), limits of cardiac nerve origin, namely the upper limit of SN and the lower limit of TN, differ among authors (Ellison and Williams 1962; Fukuyama 1982; Hausman 1956; Janes et al. 1986; Kuntz and Morehouse 1930; Mizeres 1963; Mitchell 1953; Pick 1970). In humans, based on our detailed anatomy, the upper limit of SN was clearly consistent from SG. On the other hand, the lower limit of TN is difficult to correctly identify because TN is quite slender and has a complicated course along the vessel, appearing irregularly throughout the posterior mediastinum. Tanaka et al. (2007) described the lowest origin of TN originating from 9TG in shrew (Suncus murinus) and concluded that it was similar to that in humans. Based on our comparative anatomy of ACNS (discussed later), we disagree with their conclusions that the shrew shares primitive morphologies with humans, based on numerous and significant anatomical differences between humans and other mammals including primates as well as their evolutionary divergence.
Position of cardiac plexus
Cervical part of common carotid artery (CC)
Thoracic part of CC or brachiocephalic artery
Peripheral cardiac nervous distribution
Modifications of the human ACNS in anomalous branchial arteries
Even simply in terms of developmental biology, in order to examine the unique development of arterial anomaly, it is important to understand its normal development, function, and treatment (Kasai 1962; Bergwerff et al. 1999; Molin et al. 2002). I also believe that topographical changes in the ACNS concerning surrounding vessel anomalies provide clues regarding the normal fundamental architecture, possible course of ACNS in abnormal cases, and clinical applications. In other words, this examination does not consider the morphogenesis of the arterial anomaly as noted in conventional anatomical research. Consequently, we have analyzed the extensive changes seen in the ACNS using the relatively high frequency branchial anomalies, retroesophageal right subclavian artery (RERSA) and left vertebral artery directly originating from the aortic arch (ALVA), as a model for understanding normal ACNS structure, in order to elucidate useful information for anatomists, clinicians, and developmental biologists.
Retroesophageal right subclavian artery
Anomalous left vertebral artery originating from aortic arch
Morphological significance with clinical implications
Evolutionary comparative morphology of ACNS
To understand the function and consider the clinical application of ACNS, experimental studies have employed model animals such as rats, mice, or dogs. However, ACNS morphologies show considerable interspecific differences between humans and these experimental animals. For example, the main trunk of the cervical sympathetic nerve and the vagus nerve are fused as one, vagosympathetic trunk in dogs (Nonidez 1939; Mizeres 1955, 1958). Therefore, we performed a comparative anatomical examination of ACNS in dogs and rats as a preparatory study. The morphologies in both mammals were very different from that in humans. In dogs, the main sympathetic contributor was CT comprising IG and 1TG–3TG as well as the presence of the vago-sympathetic trunk. Therefore, the main nerve supply and composition of CT are remarkably different in these species. In rats, we observed large venous differences, such as bilateral superior caval veins and left azygos arch, no SN originating from SG, no communicating branch from MG to the spinal cervical nerve, and a well-developed CT comprising IG, 1TG, and 2TG. Consequently, the experimental data obtained in typical experimental animals are difficult to apply and translate directly to humans, especially in ACNS research.
Evolution in placental mammals
Remarkably, recent molecular analysis has revised placental mammal evolution to two taxa: Boreoplacentalia and Notoplacentalia. Notoplacentalia is further divided into Xenarthra, comprising mammals such as the sloth, anteater, and armadillo; and Afroplacentalia, comprising mammals such as the elephant, manatee, hyrax, golden mole, and tenrec. On the other hand, the Boreoplacentalia is divided into Laurasiaplacentalia, comprising numerous mammals such as dog, cat, whale, horse, shrew, bear, bat, and hedgehog; and Archontoglires, comprising primates including humans, tree shrew, flying lemur, and rodents (Arnason et al. 2008).
According to recent molecular evolution research, the divergence of Euarchontoglires is estimated to have occurred 88–90 million years ago (Hedges and Kumar 2003; Janecka et al. 2007), and the basal Boreoplacentalia split between Laurasiaplacentalia and Archontoglires was dated to 99 million years ago (Arnason et al. 2008). These results show that commonly used experimental animals are remarkably distant from humans, and this is supported by our anatomy of ACNS. Therefore, it is essential that primate ACNS morphology is clarified before results from experimental animals can be translated to humans.
A short history of primate ACNS research
Although most regional anatomical studies on the peripheral nervous system in primates have focused on the relationship between the somatic peripheral nerves and muscles or somatic limb plexus for comparison with humans, the autonomic nervous system in primates is uncommon. In comparative anatomical reports of ACNS in primates, most studies have focused on the relationship between the sympathetic ganglia and the spinal nerves (van den Broek 1908; Riegele 1926; Botar 1932; Botár et al. 1950; Kolesnikov 1935; Zuckerman 1938; Sheehan and Pick 1943; Pick 1970) in addition to research on primate ACNS with the surrounding structures (Botár and Becker 1939; Riegele 1925–1926; Sonntag 1922, 1924). As noted in these studies, the ACNS in Old World monkeys and some great apes have been relatively well studied. However, findings in the other primates are sparse. For prosimians (Strepsirrhini), New World monkeys (Platyrrhini), and gibbons (Hylobatidae), only one study by van den Broek (1908), who dissected a black lemur (Lemur macaco = Eulemur macaco), a spider monkey (Ateles ater = Ateles paniscus), and a white-handed gibbon (Hylobates lar) is present. Therefore, we examined ACNS in several primate species and most genera and families [lorises and galago (Strepsirrhini), T.K. and R.W. Thorington, in preparation; New World monkeys (Platyrrhini), Kawashima et al. 2009; Old World monkeys (Cercopithedae), Kawashima and Sato 2000; Kawashima et al. 2001, 2005, 2007; gibbons (Hylobatidae), Kawashima et al. 2008; great apes (Hominoidea), T.K. et al., in preparation]. Our studies have clarified that the findings of van den Broek (1908) do not represent a common morphology in each species, family, and group.
Comparative anatomy of primate ACNS
Evolutionary morphological implication of primate ACNS
Mammalian and avian ontogenetic developmental investigations of ACNS have been presented in a number of studies (Sharner 1930; Gomez 1958; Kirby et al. 1980; Kuratani and Tanaka 1990; Kuratani et al. 1991; Roberts 1991; Verberne et al. 1998; Shoba and Tay 2000; Hildreth et al. 2009). In mouse, the parasympathetic vagal nerves are first observed in the venous porta at E10.5 (10.5 days after fertilization) and reach the heart by E12.5, whereas the innervation of the outflow (arterial porta) occurs slightly later (Hildreth et al. 2009). Sympathetic cardiac innervation has been shown to occur at later stages than parasympathetic vagal cardiac innervation (Kirby et al. 1980; Shoba and Tay 2000; Hildreth et al. 2009).
Our comparative anatomical studies show that the variable sympathetic cardiac system and the completely consistent parasympathetic vagal cardiac system within primates are associated with later mammalian ACNS ontogeny in sympathetic innervation and earlier ontogeny in parasympathetic vagal innervation (Kirby et al. 1980; Kuratani et al. 1991; Shoba and Tay 2000; Hildreth et al. 2009). Interestingly, our comparative morphological studies of the primate lineage correspond with both primate phylogeny and autonomic nervous system ontogeny (Kawashima et al. 2009).
Although somatic system components, such as bones and muscles, and their innervation, have been examined in conventional anatomical studies, recent morphological studies have naturally changed their aim and contribution from evolutionary and taxonomic biology to functional anatomy and adaptation. However, the autonomic system probably has the possibility of preserving fundamental structures related to evolution because of its homeostasis. In our series of ACNS studies, comparative morphology within the lineage was concordant with phylogeny. This suggests that the primate ACNS has preserved its evolutionary history. Therefore, it is important to understand and translate these functional experimental findings to humans. My future additional comparative anatomical study aims at further understanding for human application, developmental studies, and evolutionary biology.
I would like to devote this paper to my two directors, Prof. Dr. Hiroshi Sasaki of Tokyo Women’s Medical University and Prof. Dr. Kenji Sato of Tokyo Medical and Dental University, as a memorial to their retirement. I also thank Prof. Emeritus Dr. Tatsuo Sato and Prof. Dr. Keiichi Akita of Tokyo Medical and Dental University for their continuous instructions as well as encouragement, and Prof. Dr. Nobuhisa Hagiwara and Dr. Takatomo Nakajima of Tokyo Women’s Medical University for supplying computed tomography data from clinical cases. This research was supported by grants from the Scientific Research (KAKENHI) of the Ministry of Education, Culture, Sports Science and Technology (MEXT) (No. 16790804, 2004–2006; No. 19790985, 2007–2009), the Japan Society for the Promotion of Science (JSPS) core-to-core program HOPE (2005–2007), and the Global COE program TWMU-MERCREM (2010–2011).