The carotid body and associated tumors: updated review with clinical/surgical significance.

Purpose: The carotid body functions as a chemoreceptor and receives richer blood supply, by weight, than any other organ in the body. We review the literature regarding the anatomy, histology, and function of the carotid body and the incidence, functionality, and clinical relevance of carotid body tumors and paragangliomas. These lesions are often nonfunctional but can be associated with catecholamine secretion. Most patients are asymptomatic or present initially with a cervical mass. As the tumors grow, they can impinge on nearby cranial nerves. Although there is some debate, the dominant clinical strategy is to surgically resect these tumors as early as possible. If they are resected early, the risk of postoperative neurovascular injury is minimized. Methods: Literature search was performed using the PubMed database with focus on articles including descriptions of the carotid body and associated tumors. Results: We reviewed recent literature that related to the anatomy of the carotid body while also including carotid pargangliomas and associated diagnosis with treatment interventions. Conclusion: As the carotid body serves as a vital modulator of cardiovascular and respiratory functions, illustrates the importance of identifying potential carotid paragangliomas due its ability to impede function of the carotid body. By understanding carotid paraganglioma's distinct etiologies while also understanding proper diagnosis of tumors allows for early detection and appropriate treatment options.

Carotid body modulation in systolic heart failure from the clinical perspective.

Augmented sensitivity of peripheral chemoreceptors (PChS) is a common finding in systolic heart failure (HF). It is related to lower left ventricle systolic function, higher plasma concentrations of natriuretic peptides, worse exercise tolerance and greater prevalence of atrial fibrillation compared to patients with normal PChS. The magnitude of ventilatory response to the activation of peripheral chemoreceptors is proportional to the level of heart rate (tachycardia) and blood pressure (hypertension) responses. All these responses can be measured non-invasively in a safe and reproducible fashion using different methods employing either hypoxia or hypercapnia. Current interventions aimed at modulation of peripheral chemoreceptors in HF are focused on carotid bodies (CBs). There is a clear link between afferent signalling from CBs and sympathetic overactivity, which remains the priority target of modern HF treatment. However, CB modulation therapies may face several potential obstacles: (1) As evidenced by HF trials, an excessive inhibition of sympathetic system may be harmful. (2) Proximity of critical anatomical structures (important vessels and nerves) makes surgical and transcutaneous interventions on CB technically demanding. (3) Co-existence of atherosclerosis in the area of carotid artery bifurcation increases the risk of central embolic events related to CB modulation. (4) The relative contribution of CBs vs. aortic bodies to sympathetic activation in HF patients is unclear. (5) Choosing optimal candidates for CB modulation from the population of HF patients may be problematic. (6) There is a risk of nocturnal hypoxia following CB ablation - mostly after bilateral procedures and in patients with concomitant obstructive sleep apnoea.

Three-dimensional architectures of P2X2-/P2X3-immunoreactive afferent nerve terminals in the rat carotid body as revealed by confocal laser scanning microscopy.

We investigated the three-dimensional architectures of P2X2-/P2X3-immunoreactive nerve terminals in the rat carotid body using immunohistochemistry with confocal laser microscopy. Nerve endings immunoreactive for P2X2 and P2X3 were associated with clusters of type I cells, whereas some nerve endings were sparsely distributed in a few clusters. Most nerve endings surrounding type I cells were hederiform in shape and extended several flattened axon terminals, which were polygonal or pleomorphic in shape and contained P2X2-/P2X3-immunoreactive products. Three-dimensional reconstruction views revealed that some flattened nerve endings with P2X3 immunoreactivity formed arborized, sac- or goblet-like terminal structures and were attached to type I cells immunoreactive for tyrosine hydroxylase (TH). However, P2X3-immunoreactive axon terminals were sparsely distributed in type I cells immunoreactive for dopamine beta-hydroxylase. Multi-immunolabeling for P2X2, S100, and TH revealed that P2X2-immunoreactive axon terminals were attached to TH-immunoreactive type I cells on the inside of type II cells with S100 immunoreactivity. These results revealed the detailed morphology of P2X2-/P2X3-immunoreactive nerve terminals and suggest that sensory nerve endings may integrate chemosensory signals from clustered type I cells with their variform nerve terminals.

Care of the patient undergoing surgical excision of a carotid body chemodectoma.

The carotid body is a small mass of tissue inside the carotid bifurcation that reacts to the body's level of oxygen. In rare cases, the carotid body may develop a tumor known as a chemodectoma or paraganglioma. These tumors can vary in size and, typically, they are benign. Although carotid body tumors usually are painless and slow growing, they may cause a compression syndrome that results in symptoms such as dysphagia. The treatment of choice for many carotid body tumors is surgical removal, but there are risks involved with resecting these tumors because of their close location to the carotid vessels and cranial nerves. The use of newer imaging modalities to allow earlier detection of carotid body tumors and careful surgical technique can decrease the complications associated with this challenging surgical procedure.

The Carotid Sinus Nerve-Structure, Function, and Clinical Implications.

Interest has been renewed in the anatomy and physiology of the carotid sinus nerve (CSN) and its targets (carotid sinus and carotid body, CB), due to recent proposals of surgical procedures for a series of common pathologies, such as carotid sinus syndrome, hypertension, heart failure, and insulin resistance. The CSN originates from the glossopharyngeal nerve soon after its appearance from the jugular foramen. It shows frequent communications with the sympathetic trunk (usually at the level of the superior cervical ganglion) and the vagal nerve (main trunk, pharyngeal branches, or superior laryngeal nerve). It courses on the anterior aspect of the internal carotid artery to reach the carotid sinus, CB, and/or intercarotid plexus. In the carotid sinus, type I (dynamic) carotid baroreceptors have larger myelinated A-fibers; type II (tonic) baroreceptors show smaller A- and unmyelinated C-fibers. In the CB, afferent fibers are mainly stimulated by acetylcholine and ATP, released by type I cells. The neurons are located in the petrosal ganglion, and centripetal fibers project on to the solitary tract nucleus: chemosensory inputs to the commissural subnucleus, and baroreceptor inputs to the commissural, medial, dorsomedial, and dorsolateral subnuclei. The baroreceptor component of the CSN elicits sympatho-inhibition and the chemoreceptor component stimulates sympatho-activation. Thus, in refractory hypertension and heart failure (characterized by increased sympathetic activity), baroreceptor electrical stimulation, and CB removal have been proposed. Instead, denervation of the carotid sinus has been proposed for the "carotid sinus syndrome." Anat Rec, 302:575-587, 2019. © 2018 Wiley Periodicals, Inc.

Comparative analysis of neonatal and adult rat carotid body responses to chronic intermittent hypoxia.

Previous studies suggest that carotid body responses to long-term changes in environmental oxygen differ between neonates and adults. In the present study we tested the hypothesis that the effects of chronic intermittent hypoxia (CIH) on the carotid body differ between neonates and adult rats. Experiments were performed on neonatal (1-10 days) and adult (6-8 wk) males exposed either to CIH (9 episodes/h; 8 h/day) or to normoxia. Sensory activity was recorded from ex vivo carotid bodies. CIH augmented the hypoxic sensory response (HSR) in both groups. The magnitude of CIH-evoked hypoxic sensitization was significantly greater in neonates than in adults. Seventy-two episodes of CIH were sufficient to evoke hypoxic sensitization in neonates, whereas as many as 720 CIH episodes were required in adults, suggesting that neonatal carotid bodies are more sensitive to CIH than adult carotid bodies. CIH-induced hypoxic sensitization was reversed in adult rats after reexposure to 10 days of normoxia, whereas the effects of neonatal CIH persisted into adult life (2 mo). Acute intermittent hypoxia (IH) evoked sensory long-term facilitation of the carotid body activity (sensory LTF, i.e., increased baseline neural activity following acute IH) in CIH-exposed adults but not in neonates. The effects of CIH were associated with hyperplasia of glomus cells in neonatal but not in adult carotid bodies. These observations demonstrate that responses to CIH differ between neonates and adults with regard to the magnitude of sensitization of HSR, susceptibility to CIH, induction of sensory LTF, reversibility of the responses, and morphological remodeling of the chemoreceptor tissue.

Sensing hypoxia in the carotid body: from stimulus to response.

The carotid body is a peripheral sensory organ that can transduce modest falls in the arterial PO(2) (partial pressure of oxygen) into a neural signal that provides the afferent limb of a set of stereotypic cardiorespiratory reflexes that are graded according to the intensity of the stimulus. The stimulus sensed is tissue PO(2) and this can be estimated to be around 50 mmHg during arterial normoxia, falling to between 10-40 mmHg during hypoxia. The chemoafferent hypoxia stimulus-response curve is exponential, rising in discharge frequency with falling PO(2), and with no absolute threshold apparent in hyperoxia. Although the oxygen sensor has not been definitely identified, it is believed to reside within type I cells of the carotid body, and presently two major hypotheses have been put forward to account for the sensing mechanism. The first relies upon alterations in the cell energy status that is sensed by the cytosolic enzyme AMPK (AMP-activated protein kinase) subsequent to hypoxia-induced increases in the cellular AMP/ATP ratio during hypoxia. AMPK is localized close to the plasma membrane and its activation can inhibit both large conductance, calcium-activated potassium (BK) and background, TASK-like potassium channels, inducing membrane depolarization, voltage-gated calcium entry and neurosecretion of a range of transmitter and modulator substances, including catecholamines, ATP and acetylcholine. The alternative hypothesis considers a role for haemoxygenase-2, which uses oxygen as a substrate and may act to gate an associated BK channel through the action of its products, carbon monoxide and possibly haem. It is likely however, that these and other hypotheses of oxygen transduction are not mutually exclusive and that each plays a role, via its own particular sensitivity, in shaping the full response of this organ between hyperoxia and anoxia.

Acute oxygen sensing in heme oxygenase-2 null mice.

Hemeoxygenase-2 (HO-2) is an antioxidant enzyme that can modulate recombinant maxi-K(+) channels and has been proposed to be the acute O(2) sensor in the carotid body (CB). We have tested the physiological contribution of this enzyme to O(2) sensing using HO-2 null mice. HO-2 deficiency leads to a CB phenotype characterized by organ growth and alteration in the expression of stress-dependent genes, including the maxi-K(+) channel alpha-subunit. However, sensitivity to hypoxia of CB is remarkably similar in HO-2 null animals and their control littermates. Moreover, the response to hypoxia in mouse and rat CB cells was maintained after blockade of maxi-K(+) channels with iberiotoxin. Hypoxia responsiveness of the adrenal medulla (AM) (another acutely responding O(2)-sensitive organ) was also unaltered by HO-2 deficiency. Our data suggest that redox disregulation resulting from HO-2 deficiency affects maxi-K(+) channel gene expression but it does not alter the intrinsic O(2) sensitivity of CB or AM cells. Therefore, HO-2 is not a universally used acute O(2) sensor.

Electrical and pharmacological properties of petrosal ganglion neurons that innervate the carotid body.

The petrosal ganglion (PG) contains the somata of primary afferent neurons that innervate the chemoreceptor (glomus) cells in the carotid body (CB). The most accepted model of CB chemoreception states that natural stimuli trigger the release of one or more transmitters from glomus cells, which in turn acting on specific post-synaptic receptors increases the rate of discharge in the nerve endings of PG neurons. However, PG neurons that project to the CB represent only small fraction (roughly 20%) of the whole PG and their identification is not simple since their electrophysiological and pharmacological properties are not strikingly different as compared with other PG neurons, which project to the carotid sinus or the tongue. In addition, differences reported on the actions of putative transmitters on PG neurons may reflect true species differences. Nevertheless, some experimental strategies have contributed to identify and characterize the properties of PG neurons that innervate the CB. In this review, we examined the electrophysiological properties and pharmacological responses of PG neurons to putative CB excitatory transmitters, focusing on the methods of study and species differences. The evidences suggest that ACh and ATP play a major role in the fast excitatory transmission between glomus cells and chemosensory nerve endings in the cat, rat and rabbit. However, the role of other putative transmitters such as dopamine, 5-HT and GABA is less clear and depends on the specie studied.

Peripheral arterial chemoreceptors and the evolution of the carotid body.

There has been a reduction in the distribution of peripheral respiratory O(2) chemoreceptors from multiple, dispersed sites in fish and amphibia to a single dominant receptor site in birds and mammals. In the process, the cells in the fish gill associated with O(2) chemosensing (5-HT containing neuroepithelial cells often found in association with ACh/catecholamine (CA) containing cells) are replaced by the glomus cells of the mammalian carotid body (which contain multiple putative neurotransmitter substances, including 5-HT, CA and ACh, all within the same cells), although this difference may be more superficial than first appears. While still highly speculative, these trends would appear to be correlated with the transition from aquatic respiration and bimodal breathing, and from animals with intra-cardiac shunts (two situations where the ability to sense O(2) at multiple sites would be an advantage), to strictly air breathing in animals with no intra-cardiac shunts. It is also tempting to speculate that while the basic O(2)-sensing mechanism is the same for all receptor cells, the receptor groups in fish have evolved in such a way to make the responses of some more sensitive to changes in O(2) delivery than others. The net result is that those receptors associated with the first gill arch of fish (the third branchial arch) become the carotid body in higher vertebrates associated with the regulation of ventilation and ensuring oxygen supply to the gas exchange surface. Those receptors associated with the second gill arch (fourth branchial arch) become the aortic bodies capable of sensing changes in oxygen content of the blood and primarily involved in regulating oxygen transport capacity through erythropoiesis and changes in blood volume.

Autonomic innervation of the carotid body: role in efferent inhibition.

The carotid body (CB) is a chemosensory organ that monitors blood chemicals and initiates compensatory reflex adjustments to maintain homeostasis. The 'afferent' sensory discharge induced by changes in blood chemicals, e.g. low PO(2) (hypoxia), is relayed by carotid sinus nerve (CSN) fibers and has been well studied. Much less is known, however, about a parallel autonomic (parasympathetic) 'efferent' pathway that is the source of CB inhibition. This pathway is the focus of this review which begins with a historical account of the early findings and links them to more recent data on the source of this innervation, and the role of endogenous neurotransmitters in efferent inhibition. We review evidence that these autonomic neurons are embedded in 'paraganglia' within the glossopharyngeal (GPN) and CSN nerves, and for the role of nitric oxide (NO) in mediating efferent inhibition. Finally, we discuss recent data linking the action of hypoxia and a key CB neurotransmitter, i.e. ATP, to potential mechanisms for activating this efferent pathway.

Control of breathing and ventilatory acclimatization to hypoxia in deer mice native to high altitudes.

AIM: We compared the control of breathing and heart rate by hypoxia between high- and low-altitude populations of Peromyscus mice, to help elucidate the physiological specializations that help high-altitude natives cope with O2 limitation. METHODS: Deer mice (Peromyscus maniculatus) native to high altitude and congeneric mice native to low altitude (Peromyscus leucopus) were bred in captivity at sea level. The F1 progeny of each population were raised to adulthood and then acclimated to normoxia or hypobaric hypoxia (12 kPa, simulating hypoxia at ~4300 m) for 5 months. Responses to acute hypoxia were then measured during stepwise reductions in inspired O2 fraction. RESULTS: Lowlanders exhibited ventilatory acclimatization to hypoxia (VAH), in which hypoxia acclimation enhanced the hypoxic ventilatory response, made breathing pattern more effective (higher tidal volumes and lower breathing frequencies at a given total ventilation), increased arterial O2 saturation and heart rate during acute hypoxia, augmented respiratory water loss and led to significant growth of the carotid body. In contrast, highlanders did not exhibit VAH - exhibiting a fixed increase in breathing that was similar to hypoxia-acclimated lowlanders - and they maintained even higher arterial O2 saturations in hypoxia. However, the carotid bodies of highlanders were not enlarged by hypoxia acclimation and were similar in size to those of normoxic lowlanders. Highlanders also maintained consistently higher heart rates than lowlanders during acute hypoxia. CONCLUSIONS: Our results suggest that highland deer mice have evolved high rates of alveolar ventilation and respiratory O2 uptake without the significant enlargement of the carotid bodies that is typical of VAH in lowlanders, possibly to adjust the hypoxic chemoreflex for life in high-altitude hypoxia.

Current concepts for the surgical management of carotid body tumor.

BACKGROUND: Carotid body tumor (CBT) is a rare lesion of the neuroendocrine system. Chronic hypoxia has long been recognized as an etiology of CBT and other paragangliomas. Recent biogenetic discoveries reveal that mutations in oxygen-sensing genes are another etiology, accounting for approximately 35% of cases, and that these 2 etiologies are probably additive. DATA SOURCES: (1) A retrospective analysis of fifteen cases of CBT in a 6-year period occurring in the mountains of Southern Appalachia; (2) an extensive review of the literature on the surgery of CBT and on the expansive biogenetic understanding of the disease. CONCLUSIONS: Improved imaging, vascular surgical techniques, and understanding of the disease have vastly improved outcomes for patients. The necessities for long-term follow-up and appropriate genetic testing and counseling of patients and their families are documented. Surgeon and institutional competence are critical in achieving maximal outcomes.

Modulation of emetic response by carotid baro- and chemoreceptor activations.

We hypothesized that baroreceptor or chemoreceptor activation might be involved in the emetic, and prodromal cardiovascular and respiratory responses. To test this hypothesis, we induced the emetic responses by gastric distension in anesthetized Suncus murinus (house musk shrew), that had intact and absent baroreceptor and chemoreceptor afferents. Secondly, we stimulated the aortic depressor nerve (ADN) and the carotid sinus nerve (CSN) with or without gastric distension. Internal carotid artery ligation in the bifurcation area, which abolished reflex bradycardia by baroreceptor activation, and abolition of chemoreceptor reflex bradycardia and hyperventilation, by carotid body denervation, suppressed the emetic response but did not abolish it. ADN denervation, which produced no significant effects on the baroreceptor or chemoreceptor reflex bradycardia, had no effect on the emetic response, including the prodromal phase. CSN stimulation with gastric distension elicited retching accompanied by reflex bradycardia and hypotension during or just after stimulation, whereas ADN stimulation with gastric distension did not induce the cardiovascular reflex, and had no effects on the emetic response. These results indicate that carotid, rather than aortic, baroreceptor or chemoreceptor activation plays an important role in the augmentation of cardiac parasympathetic activity and the development of emetic response. In conclusion, carotid baroreceptor or chemoreceptor activation, which is non-emetic stimulation, acts as a modulator in the central mechanisms of emesis.

Microsurgical anatomy of the human carotid body (glomus caroticum): Features of its detailed topography, syntopy and morphology.

The human glomus caroticum (GC) is not readily accessible during ordinary anatomical teaching courses because of insufficient time and difficulties encountered in the preparation. Accordingly, most anatomical descriptions of its location, relationship to neighboring structures, size and shape are supported only by drawings, but not by photographs. The aim of this study is to present the GC with all associated roots and branches. Following microscope-assisted dissection and precise photo-documentation, a detailed analysis of location, syntopy and morphology was performed. We carried out this study on 46 bifurcations of the common carotid artery (CCA) into the external (ECA) and internal (ICA) carotid arteries and identified the GC in 40 (91%) of them. We found significant variations regarding the location of the GC and its syntopy: GC was associated with CCA (42%), ECA (28%) and ICA (30%) lying on the medial or lateral surface (82% or 13%, respectively) or exactly in the middle (5%) of the bifurcation. The short and long diameter of its oval form varied from 1.0 × 2.0 to 5.0 × 5.0mm. Connections with the sympathetic trunk (100%), glossopharyngeal (93%), vagus (79%) and hypoglossal nerve (90%) could be established in 29 cadavers. We conclude that precise knowledge of this enormous variety might be very helpful not only to students in medicine and dentistry during anatomical dissection courses, but also to surgeons working in this field.

Morphometric investigation of carotid body in sudden infant death syndrome.

BACKGROUND: The pathomechanism of sudden infant death syndrome (SIDS) has not been clarified yet. The high rate of early progenitor cells in carotid body has been reported as a pathognomic feature for SIDS. AIM AND STUDY DESIGN: The morphometric analysis was done by NIKON Eclipse microscope with a morphometric program Lucia G. SUBJECTS: This study was designed to investigate the structure and developmental state of carotid body in SIDS and non-SIDS cases. A comparison was made between the rates of dark and early progenitor cells. OUTCOME MEASURES: The Kruskal-Wallis test showed a significantly higher number of progenitor cells in the SIDS group than in controls (p=0.0003). RESULTS AND CONCLUSION: In this study on Hungarian SIDS cases we confirmed the observation that infants who died suddenly have an underdeveloped carotid body.

Calcitonin gene-related peptide immunoreactivity in the nucleus of the tractus solitarius and the carotid receptors of the cat originates from peripheral afferents.

The presence and distribution of the calcitonin gene-related peptide was studied, using immunohistochemical techniques, in carotid receptors, in the nodose and glossopharyngeal ganglia and in the nucleus tractus solitarii of the cat. Seventy-seven per cent of the 42% of the nodose ganglion cells were labeled. Fine, sparsely branched immunoreactive terminal axonal arborizations were found in the carotid body; they disappeared after petrosal ganglionectomy. The intense immunoreactivity present in fibers in the commissural, medial, interstitial, gelatinosus, dorsal, intermediate and rostral gustatory subnuclei of the nucleus tractus solitarius was drastically reduced after removal of the ipsilateral nodose and petrosal ganglia. The central distribution of the immunoreactive axons, the morphology of the terminals in the carotid receptors and their dependence on an intact peripheral innervation are consistent with the idea that in the cat the calcitonin gene-related peptide is present in a high proportion of the primary visceral afferents, most of them unmyelinated.

Localization and actions of nitric oxide in the cat carotid body.

An extensive plexus of nerve fibers capable of synthesizing nitric oxide was demonstrated in the cat carotid body by immunocytochemical and biochemical studies of nitric oxide synthase. Denervation experiments indicated that the axons originate from: (i) microganglial neurons located within the carotid body and along the glossopharyngeal and carotid sinus nerves, whose ramifications primarily innervate carotid body blood vessels; and (ii), sensory neurons in the petrosal ganglion, whose terminals end in association with lobules of type I cells. In the in vitro superfused cat carotid body, the nitric oxide synthase substrate, L-arginine, induced a dose-dependent inhibition of carotid sinus nerve discharge evoked by hypoxia. In contrast, the nitric oxide synthase inhibitor, L-NG-nitroarginine methylester, augmented the chemoreceptor response to hypoxia, and this effect was markedly enhanced when the preparation was both perfused and superfused in vitro. The nitric oxide donor, nitroglycerine, inhibited carotid sinus nerve discharge, and immunocytochemistry revealed that this drug stimulated the formation of cyclic 3',5'-guanosine monophosphate in both type I cells and blood vessels. Our data indicate that nitric oxide is an inhibitory neuronal messenger in the carotid body, which affects the process of chemoreceptor transduction/transmission via actions on both the receptor elements and their associated blood vessels.

Carotid body hypertrophy in patients with cystic fibrosis and cyanotic congenital heart disease.

The carotid bodies from 71 patients ranging in age from 28 weeks' gestation to 30 years were obtained at autopsy. Patients were divided into two groups based on the presence or absence of chronic hypoxemia. There was a high correlation between the weight of individual carotid bodies in each case. Among the 12 patients with chronic hypoxemia, eight patients had carotid bodies heavier than predicted by statistical analysis. Of these eight patients, six had cystic fibrosis and two had cyanotic heart disease. Morphometric and cell population analyses of the carotid bodies from these eight patients and from those of the control population indicated that enlargement of the carotid bodies during normal or abnormal growth results from proportionate increases in lobule parenchyma and stroma. There was also an increase in the width and length of the lobules without an increase in the diameter of the cell cords or a change in the size or proportion of the chief cells. Growth and development of the carotid bodies were studied in a control group of 59 patients without chronic hypoxemia. There were no sex related differences in carotid body weights. The combined weight of the carotid bodies correlated most strongly with body weight, although there was some correlation with age and body length. A regression equation reflecting the data relating to body weight (BW) is: Combined weight of carotid bodies (in mg.) = 0.29 BW (in kg.) +3.0. Leukemic infiltrates were present in two patients with acute lymphocytic leukemia, and diffuse lymphocytic infiltration with nodule formation was present in one patient with mental retardation. Metaplastic cartilage was present in a carotid body of one patient.

Anatomical variations in human carotid bodies.

The variations in anatomical structure and position of both carotid bodies were noted in 100 consecutive subjects who came to necropsy. Considerable variations in form were found. Although most carotid bodies (83% on the right and 86% on the left) were of the classic ovoid type, an appreciable minority was bilobed (9% on the right and 7% on the left) or double (7% on the right and 6% on the left); 1% were leaf shaped. All these anatomical variants have to be distinguished from the pathologically enlarged carotid body that may have a smooth or finely nodular surface. Anatomical variants (such as the bilobed) may themselves enlarge as a consequence of carotid body hyperplasia.