Three-Dimensional Ultrastructure of Flower-Spray Nerve Endings in the Rat Carotid Sinus.

The flower-spray nerve endings are afferent nerve terminals in the carotid sinus that arise from carotid sinus nerve of glossopharyngeal nerve. However, the three-dimensional ultrastructural characteristics of flower-spray nerve endings and spatial relationships between the terminal parts and other cellular elements have not been fully understood. To elucidate their detailed relationship, backscattered electron imaging of serial sections was performed with a scanning electron microscope to produce a three-dimensional reconstruction of the flower-spray endings. The terminal parts of flower-spray endings were distributed horizontally approximately 5 µm outside the external elastic membrane in the tunica adventitia of the internal carotid artery. The three-dimensional reconstruction showed that the terminal parts of flower-spray endings were flat with irregular contours and were partially covered by the thin cytoplasmic processes of Schwann cells. The complex consisting of the nerve terminals and associated Schwann cells was surrounded by a multilayered basement membrane. The terminal parts of the endings were also surrounded by fibroblasts with elastic fibers and collagen fibrils. Secretory vesicles without an electron-dense core were observed in the terminal parts of the endings. The accumulation of vesicles just below the axonal membrane was observed in terminal parts not covered by Schwann cell cytoplasmic processes on both the luminal and basal sides. Swollen mitochondria, concentric membranous structures, and glycogen granule-like electron-dense materials were often noted in some of the terminal parts of the endings and the parent axon. Collectively, the present results suggest that flower-spray endings are baroreceptors because their morphology was similar to other mechanoreceptors. Furthermore, flower-spray endings may be affected by glutamate secreted in an autocrine manner.

Effects of acute carotid baroreceptor stimulation on sympathetic nerve traffic in resistant and uncontrolled hypertension: a systematic review and meta-analysis.

In resistant hypertensive patients acute carotid baroreflex stimulation is associated with a blood pressure (BP) reduction, believed to be mediated by a central sympathoinhbition.The evidence for this sympathomodulatory effect is limited, however. This meta-analysis is the first to examine the sympathomodulatory effects of acute carotid baroreflex stimulation in drug-resistant and uncontrolled hypertension, based on the results of microneurographic studies. The analysis included 3 studies assessing muscle sympathetic nerve activity (MSNA) and examining 41 resistant uncontrolled hypertensives. The evaluation included assessment of the relationships between MSNA and clinic heart rate and BP changes associated with the procedure. Carotid baroreflex stimulation induced an acute reduction in clinic systolic and diastolic BP which achieved statistical significance for the former variable only [systolic BP: -19.98 mmHg (90% CI, -30.52, -9.43), P < 0.002], [diastolic BP: -5.49 mmHg (90% CI, -11.38, 0.39), P = NS]. These BP changes were accompanied by a significant MSNA reduction [-4.28 bursts/min (90% CI, -8.62, 0.06), P < 0.07], and by a significant heart rate decrease [-3.65 beats/min (90% CI, -5.49, -1.81), P < 0.001]. No significant relationship was detected beween the MSNA, systolic and diastolic BP changes induced by the procedure, this being the case also for heart rate. Our data show that the acute BP lowering responses to carotid baroreflex stimulation, although associated with a significant MSNA reduction, are not quantitatively related to the sympathomoderating effects of the procedure. This may suggest that these BP effects depend only in part on central sympathoinhibition, at least in the acute phase following the intervention.

Carotid sinus baroafferent signals contribute to cerebral blood flow regulation during acute hypotension in young males: A randomized crossover study.

Cerebral autoregulation is an important factor in prevention of cerebral ischemic events. We tested a traditional but unproven hypothesis that carotid sinus baroafferent signals contribute to dynamic cerebral autoregulation. Middle cerebral artery mean blood velocity (MCA Vmean ) responses to thigh-cuff deflation-induced acute hypotension were compared between conditions using neck suction soon after cuff deflation, without or with a cushion wrapped around the upper neck, in nine healthy males (aged 25 ± 5 years). Neck suction was applied close to the hypotension. The MCA Vmean response was expected to differ between conditions because the cushion was presumed to prevent the carotid sinus distension by neck suction. The cushion hindered bradycardia and depressor responses during sole neck suction. Thigh-cuff deflation decreased mean arterial blood pressure (MAP) and MCA Vmean (Ps < 0.05) with an almost unchanged respiratory rate under both conditions. However, in the neck suction + cushion condition, subsequent MCA Vmean restoration was faster and greater (Ps ≤ 0.0131), despite similar changes in MAP in both conditions. Thus, carotid sinus baroafferent signals would accelerate dynamic cerebral autoregulation during rapid hypotension in healthy young males. Elucidating the mechanism underlying cerebral neural autoregulation could provide a new target for preventing cerebral ischemic events.

The effect of carotid sinus neurectomy for carotid restenosis: a study protocol for a double-blinded and randomized controlled trial.

BACKGROUND: Patients undergoing carotid endarterectomy (CEA) have a high restenosis rate, which increases the risk of stroke, and there is still a lack of effective treatment for restenosis. The cause of stenosis is related to local inflammatory reactions. Some basic studies have shown that the inflammatory response causing arterial stenosis is closely related to the nerve axons distributed in its outer membrane, and that removal of the nerve is effective in reducing the inflammatory response to prevent arterial stenosis. Therefore, we propose to design a randomized controlled trial to study whether disconnecting the carotid sinus nerve during a CEA operation can reduce carotid arterial restenosis. METHOD/DESIGN: This study is a randomized, double-blind, single-center study. We will recruit 276 patients, who will be randomly divided into the experimental group and the control group. Based on the standard CEA operation, the operator will search for the carotid sinus nerve on the surface of the internal carotid artery and will entirely transect it in the experimental group. Both groups will be guided with the same postoperative treatment and will be followed up every 3 months for 3 years after the operation. The main indices observed will be the carotid restenosis rate, incidence and nature of carotid plaque, and carotid blood flow velocity. Other indices will be arrhythmia, blood pressure variability, and biomarkers of atherosclerosis, such as blood lipids, hypersensitive C-reactive protein (hs-CRP), homocysteine, and total bilirubin. DISCUSSION: It is expected that carotid sinus nerve transection will significantly reduce the occurrence of restenosis after CEA, decrease the incidence of ischemic stroke, and realize the effective primary prevention of stroke. TRIAL REGISTRATION: ChiCTR2300073652. Registered on July 18, 2023.

Input-size dependence of the baroreflex neural arc transfer characteristics during Gaussian white noise inputs.

Although Gaussian white noise (GWN) inputs offer a theoretical framework for identifying higher-order nonlinearity, an actual application to the data of the neural arc of the carotid sinus baroreflex did not succeed in fully predicting the well-known sigmoidal nonlinearity. In the present study, we assumed that the neural arc can be approximated by a cascade of a linear dynamic (LD) component and a nonlinear static (NS) component. We analyzed the data obtained using GWN inputs with a mean of 120 mmHg and standard deviations (SDs) of 10, 20, and 30 mmHg for 15 min each in anesthetized rats (n = 7). We first estimated the linear transfer function from carotid sinus pressure to sympathetic nerve activity (SNA) and then plotted the measured SNA against the linearly predicted SNA. The predicted and measured data pairs exhibited an inverse sigmoidal distribution when grouped into 10 bins based on the size of the linearly predicted SNA. The sigmoidal nonlinearity estimated via the LD-NS model showed a midpoint pressure (104.1 ± 4.4 mmHg for SD of 30 mmHg) lower than that estimated by a conventional stepwise input (135.8 ± 3.9 mmHg, P < 0.001). This suggests that the NS component is more likely to reflect the nonlinearity observed during pulsatile inputs that are physiological to baroreceptors. Furthermore, the LD-NS model yielded higher R2 values compared with the linear model and the previously suggested second-order Uryson model in the testing dataset.NEW & NOTEWORTHY We examined the input-size dependence of the baroreflex neural arc transfer characteristics during Gaussian white noise inputs. A linear dynamic-static nonlinear model yielded higher R2 values compared with a linear model and captured the well-known sigmoidal nonlinearity of the neural arc, indicating that the nonlinear dynamics contributed to determining sympathetic nerve activity. Ignoring such nonlinear dynamics might reduce our ability to explain underlying physiology and significantly limit the interpretation of experimental data.

Electrical carotid sinus nerve stimulation attenuates experimental colitis induced by acetic acid in rats.

AIMS: The carotid bodies are sensors that detect physiological signals and convey them to the central nervous system, where the stimuli are processed inducing reflexes through efferent pathways. Recent studies have demonstrated that electrical stimulation of the carotid sinus nerve (CSN) triggers the anti-inflammatory reflex under different conditions. However, whether this electrical stimulation attenuates colitis was never examined. This study aimed to evaluate if the electrical CSN stimulation attenuates the experimental colitis induced by intrarectal administration of acetic acid in rats. METHODS: Electrodes were implanted around the CSN to stimulate the CSN, and a catheter was inserted into the left femoral artery to record the arterial pressure. The observation of hypotensive responses confirmed the effectiveness of the electrical CNS stimulation. This maneuver was followed by a 4 % acetic acid or saline administered intrarectally. After 24 h, colons were segmented into distal and proximal parts for macroscopy, histological and biochemical assessment. KEY FINDINGS: As expected, the electrical CSN stimulation was effective in decreasing arterial pressure in saline and colitis rats. Moreover, electrical CSN stimulation effectively reduced colonic tissue lesions, colitis scores, and histopathologic parameters associated with colitis. In addition, the CSN stimulation also reduced the colonic mucosa pro-inflammatory cytokine interleukin-1 beta, and increased the anti-inflammatory interleukin-10, in rats submitted to colitis. SIGNIFICANCE: These findings indicated that electrical CSN stimulation breaks the vicious cycle of local colon inflammation in colitis, which might contribute to its better outcome.

Novel approaches: targeting sympathetic outflow in the carotid sinus.

Uncontrolled hypertension drives the global burden of increased cardiovascular disease (CVD) morbidity and mortality. Although high blood pressure (BP) is treatable and preventable, only half of the patients with hypertension undergoing treatment have their BP controlled. The failure of polypharmacy to attain adequate BP control may be due to a lack of physiological response, however, medication non-adherence and clinician inertia to increase treatment intensity are critical factors associated with poor hypertension management. The long-time medication titration, lifelong drug therapy, and often multi-drug treatment strategy are frustrating when the BP goal is not achieved, leading to increased CVD risk and a substantial burden on the healthcare system. Growing evidence indicates that neurohumoral activation is critical in initiating and maintaining elevated BP and its adverse consequences. Over the past decades, device-based therapies targeting the mechanisms underlying hypertension pathophysiology have been extensively studied. Among these, robust clinical experience for hypertension management exists for renal denervation (RDN) and baroreflex activation therapy (BAT), carotid body denervation (CBD), central arteriovenous anastomosis, and to a lesser extent, deep brain stimulation. Future studies are warranted to define the role of device-based approaches as an alternative or adjunctive treatment option to treat hypertension.

Systemic hypertension is a growing contributor to global disease burden and premature cause of death worldwide.The percentage of patients achieving target BP levels remains largely inadequate.Hypertension is characterised by activation of the sympathetic nervous system, with the magnitude depending on age and the disease severity.Device-based interventions have been extensively studied to directly target the relevant sympathetic neural pathophysiological mechanisms involved in BP control.Modulation of the chronic sympathetic outflow with CBD or BAT shows promise for the treatment of poorly controlled hypertension in addition to antihypertensive medicines.The BP response to device-based therapies appears variable and cannot be predicted before the procedure.Until more robust evidence related to patient selection, procedural and technical aspects is available, chemoreflex and baroreflex neuromodulation therapy should be restricted to randomised sham-controlled trials performed in experienced centres.

Chronic Metformin Administration Does Not Alter Carotid Sinus Nerve Activity in Control Rats.

Metformin is a glucose-lowering, insulin-sensitizing drug that is commonly used in the treatment of type 2 diabetes (T2D). In the last decade, the carotid body (CB) has been described as a metabolic sensor implicated in the regulation of glucose homeostasis, being CB dysfunction crucial for the development of metabolic diseases, such as T2D. Knowing that metformin could activate AMP-activated protein kinase (AMPK) and that AMPK has been described to have an important role in CB hypoxic chemotransduction, herein we have investigated the effect of chronic metformin administration on carotid sinus nerve (CSN) chemosensory activity in basal and hypoxic and hypercapnic conditions in control animals. Experiments were performed in male Wistar rats subjected to 3 weeks of metformin (200 mg/kg) administration in the drinking water. The effect of chronic metformin administration was tested in spontaneous and hypoxic (0% and 5% O2) and hypercapnic (10% CO2) evoked CSN chemosensory activity. Metformin administration for 3 weeks did not modify the basal CSN chemosensory activity in control animals. Moreover, the CSN chemosensory response to intense and moderate hypoxia and hypercapnia was not altered by the chronic metformin administration. In conclusion, chronic metformin administration did not modify chemosensory activity in control animals.

A comparison of four common mathematical models to assess baroreflex sensitivity.

Different methods have been used to assess baroreflex gain in experiments where changes in the carotid sinus pressure or the arterial blood pressure using different techniques provoke a baroreflex response, usually a rapid variation of heart rate. Four mathematical models are most used in the literature: the linear regression, the piecewise regression, and two different four-parameter logistic equations: equation 1, Y = (A1-D1)/[1 + eB1(X - C1) ] + D1; equation 2, Y = (A2-D2)/[1 + (X/C2)B2 ] + D2. We compared the four models regarding the best fit to previously published data in all vertebrate classes. The linear regression had the worst fit in all cases. The piecewise regression generally exhibited a better fit than the linear regression, though it returned a similar fit when no breakpoints were found. The logistic equations showed the best fit among the tested models and were similar to each other. We demonstrate that equation 2 is asymmetric and the level of asymmetry is accentuated according to B2. This means that the baroreflex gain calculated when X = C2 is different from the actual maximum gain. Alternatively, the symmetric equation 1 returns the maximum gain when X = C1. Furthermore, the calculation of baroreflex gain using equation 2 disregards that baroreceptors may reset when individuals experience different mean arterial pressures. Finally, the asymmetry from equation 2 is a mathematical artifact inherently skewed to the left of C2, thus bearing no biological meaning. Therefore, we suggest that equation 1 should be used instead of equation 2.

Cardioneuroablation for treatment of carotid sinus syndrome secondary to oropharyngeal squamous cell cancer.

Head and neck tumors can rarely cause carotid sinus syndrome and this often resolves by surgical intervention or palliative chemoradiotherapy. If these modalities are not an option or are ineffective, the most preferred treatment is permanent pacemaker therapy. Here, we present the first case of cardioneuroablation treatment performed in patient with oropharyngeal squamous cell cancer who developed recurrent asystole and syncope attacks due to compression of the carotid sinus on neck movement.

Convulsive Syncope From Carotid Sinus Syndrome as a Manifestation of Laryngeal Cancer.

OBJECTIVE: Carotid sinus syndrome (CSS) is a rare yet serious presentation of head and neck malignancy. To our knowledge, syncope and seizure-like episodes as a manifestation of carotid sinus syndrome secondary to laryngeal cancer has not been reported to date. We report a case of laryngeal cancer causing convulsive syncope masquerading as seizures due to CSS. METHODS: Case report. The patient's medical record was reviewed for demographic and clinical information. RESULTS: A 62-year-old male presented with multiple episodes of syncope and hoarseness of voice. On nasoendoscopic examination, left vocal cord palsy and left aryepiglottic fold tumor were visualized. Computerized tomography (CT) neck showed a large 2.4 × 3.6 cm left supraglottic tumor with local invasion and extensive cervical lymphadenopathy compressing the carotid sinus. CT guided biopsy of the tumor revealed invasive squamous cell carcinoma. While undergoing evaluation, the patient developed seizure-like episodes. Inpatient telemetry monitoring revealed significant bradycardia and hypotension during these episodes. A permanent pacemaker was inserted which resulted in resolution of the syncopal and seizure-like episodes. CONCLUSION: In patients with unexplained syncope or seizure-like episodes and a background of head and neck cancer, clinicians should consider the diagnosis of CSS. CSS is a poor prognostic factor due to the associated higher stage of disease.

A syncope collared / A "nyakon fogott" syncope esete

Carotid sinus syncope is a temporary, exaggerated circulatory response to carotid massage, characterized by marked drop in arterial pressure, and varying degree of bradycardia, or even asystole lasting for several seconds, resulting in short lasting loss of consciousness. A related reflex mediated disorder is a fainting precipitated by a parapharyngeal space-occupying lesion, manifests in prolonged episodes of hemodynamic instability. We report a case, where the hemodynamic features of the syncope are well documented. The case illustrates the potential overlap between pulseless electrical activity and syncope, and a simple noninvasive solution for the frightening symptoms is also suggested.

Relationship between annular calcification of plaques in the carotid sinus and perioperative hemodynamic disorder in carotid angioplasty and stenting.

OBJECTIVE: To investigate the correlation between annular plaque calcification in the carotid sinus and perioperative hemodynamic disorder (HD) in carotid angioplasty and stenting (CAS). METHODS: The clinical data of 49 patients undergoing CAS due to narrowing of the carotid sinus were retrospectively analyzed. All patients had preoperative carotid computed tomography angiography (CTA) and were divided into HD and non-HD groups based on the occurrence of HD in the perioperative period of CAS. HD was defined as persistent bradycardia (heart rate < 60 beats per min) or persistent hypotension (systolic blood pressure < 90 mmHg) in the perioperative period and lasting for at least 1 h. The baseline data, including the degree of carotid artery stenosis, plaque length, plaque thickness, calcified plaque morphologies (i.e., plaque circumferential angle: < 90° defined as dotted calcification; 90°-180° defined as arcuate calcification; > 180° defined as annular calcification), contralateral carotid artery conditions, balloon diameter, and stent types, were compared between the two groups. Binary logistic regression was used to analyze the risk factors for the occurrence of HD. RESULTS: Among the 49 patients undergoing CAS, 14 (28.57%) developed perioperative HD, and 35 did not. Annular calcification was more common in the patients in the HD group than in the non-HD group. No significant differences in the probabilities of dotted and arcuate calcifications were found between the two groups (p > 0.05). The duration of continuous dopamine consumption in the HD group was 9-71 h. The average hospital stay of the HD group (10.14 ± 4.17 days) was significantly longer than that of the non-HD group (6.57 ± 1.9 days; p < 0.001). Patients in the HD group had significantly more pronounced lumen stenosis (p = 0.033) and longer plaque length (p = 0.034) than those in the non-HD group. After adjusting for age and sex, multivariate regression analysis showed that the presence of annular plaque calcification was an independent predictor of HD (odds ratio: 7.68, 95% confidence interval: 1.46-40.37, p = 0.016). CONCLUSIONS: The occurrence of annular plaque calcification in the carotid sinus was an independent risk factor for perioperative HD in CAS. Preoperative carotid CTA assists with the early identification of high-risk patients who may develop HD.

Linear and nonlinear identification of the carotid sinus baroreflex in the very low-frequency range.

Since the arterial baroreflex system is classified as an immediate control system, the focus has been on analyzing its dynamic characteristics in the frequency range between 0.01 and 1 Hz. Although the dynamic characteristics in the frequency range below 0.01 Hz are not expected to be large, actual experimental data are scant. The aim was to identify the dynamic characteristics of the carotid sinus baroreflex in the frequency range down to 0.001 Hz. The carotid sinus baroreceptor regions were isolated from the systemic circulation, and carotid sinus pressure (CSP) was changed every 10 s according to Gaussian white noise with a mean of 120 mmHg and standard deviation of 20 mmHg for 90 min in anesthetized Wistar-Kyoto rats (n = 8). The dynamic gain of the linear transfer function relating CSP to arterial pressure (AP) at 0.001 Hz tended to be greater than that at 0.01 Hz (1.060 ± 0.197 vs. 0.625 ± 0.067, p = 0.080), suggesting that baroreflex control was largely maintained at 0.001 Hz. Regarding nonlinear analysis, a second-order Uryson model predicted AP with a higher R2 value (0.645 ± 0.053) than a linear model (R2  = 0.543 ± 0.057, p = 0.025) or a second-order Volterra model (R2  = 0.589 ± 0.055, p = 0.045) in testing data. These pieces of information may be used to create baroreflex models that can add a component of autonomic control to a cardiovascular digital twin for predicting acute hemodynamic responses to treatments and tailoring individual treatment strategies.