Novel approaches: targeting sympathetic outflow in the carotid sinus

Abstract 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. SUMMARY 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.

• 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.

Sympathetic outflow and hypertension
It is well established that sympathetic nervous system activation is common in patients with hypertension and critical in initiating and maintaining BP elevation [1][2][3].However, the syndrome of neurogenic essential hypertension appears to account for at least 50% of all cases of high BP, based on an estimate of the proportion of patients with essential hypertension who have demonstrable sympathetic activation, and the number of patients who achieved substantial reduction in BP with antiadrenergic drugs or devices therapy [4].Furthermore, the syndrome of neurogenic hypertension when exists in individual patients with essential hypertension is differentiated, not necessarily involving all sympathetic outflows equally [5], suggesting that the pathophysiology of hypertension is complex, particularly when searching for predictors of BP response to device-based therapies for the treatment of hypertension.
The importance of sympathetic origin as a critical mechanism underlying hypertension pathophysiology [6] is that emerging therapies have been developed to target sympathetic nervous system activity beyond neural control of the kidney where the RDN approach is specifically applied.Two device-based therapies for hypertension management have been developed to attenuate sympathetic outflow at the level of the carotid sinus.One therapeutic approach includes targeting the carotid body, a chemoreceptor organ that is involved in respiratory and cardiovascular control through complex neural pathways [7].The second device-based approach is electrical or mechanical stimulation of carotid sinus baroreceptors whose sensitivity is reset in established hypertension, to a higher pressure and reduced in gain, to mediate changes in sympathetic activity to the heart and blood vessels [8].

Anatomy and physiology of the carotid body
The carotid body is a rice-grain-sized sensory organ located bilaterally in the adventitia of the bifurcation of the common carotid artery, playing an important physiological role (i.e.swimming, ascending high altitude) in modulating cardiovascular and respiratory function through sympathetic tone, response to changes in arterial oxygen (O 2 ) or carbon dioxide (CO 2 ) levels [9,10].In pathological conditions (i.e.hypertension, obstructive sleep apnoea (OSA), chronic kidney disease, heart failure) the activity of chemoreflex is altered contributing to disease development and progression and independently predicted adverse outcomes.
The carotid body is innervated by the carotid sinus nerve (Hering's nerve), a carotid branch of the glossopharyngeal nerve (IX cranial nerve), as illustrated in Figure 1.Hering's nerve contains afferent fibres from chemoreceptors in the carotid body and baroreceptors in the carotid sinus wall.Electrical or mechanical stimulation of the carotid body results in sinus Hering's reflex causing bradycardia and arterial hypotension [11].
The peripheral arterial chemoreceptors are located in the carotid and aortic bodies, and respond primarily to changes in oxygen levels (hypoxia), while central chemoreceptors are located on the ventral surface of the medulla oblongata and primarily respond to changes in carbon dioxide (CO 2 ) levels (hypercapnia) [10,12].Activation of afferent impulses from the carotid chemoreceptors in response to hypoxia leads to simultaneous activation of the cardiorespiratory centre in the medulla oblongata (synapsing to neurons in the caudal, commissural nucleus tractus solitarius, NTS) resulting in simultaneous hyperventilation and selective peripheral vasoconstriction (increased sympathetic activity to blood vessels).At the same time, hyperventilation through a stretch of thoracic afferents elicits an inhibitory or buffering influence on the autonomic response to hypoxaemia resulting in bradycardia, mediated by increased cardiac vagal outflow (Figure 2).

Interaction of the baroreflex and the peripheral chemoreflex
The chemoreflex plays an important role in cardiovascular control, sympathetic activation, and subsequent BP elevation [10].It should be emphasised that there is a close interaction between arterial baroreceptors and peripheral chemoreceptors in the regulation of sympathetic nerve activity, suggesting convergence of baroreceptor and peripheral chemoreceptor afferents on neurons in the medulla oblongata.In healthy humans, activation of baroreflexes by an increase in BP exhibits a protective inhibitory sympatho-excitatory response to stimulation of peripheral chemoreflex by hypoxia [13], whereas, in pathological conditions, the inter-related mechanisms are altered, leading to augmented sympathetic activation and adverse CVD sequelae.

Peripheral chemoreflex in human hypertension
Carotid body hyperactivation leads to sympathetic activation, a mechanism for both initiating and sustaining elevated BP [7].Potentiated sensitivity of peripheral arterial chemoreceptors has been suggested as an important causative mechanism leading to increased sympathetic activity in hypertension.Studies performed by Polish physiologist and neurophysiologist Professor Andrzej Trzebski et al. in the early 1980s for the first time demonstrated the contribution of increased sensitivity of arterial chemoreceptors to the pathogenesis of human hypertension [14].In this study, 20 young hypertensive patients with diastolic BP were compared to age-matched controls.A novel finding was that responses to hypoxia and hypercapnia were significantly related in normotensive subjects but not in hypertensive males, suggesting that peripheral (not central) chemosensitivity is predominantly implicated in the early course of hypertension.This concept was supported by microneurography studies demonstrating that an increase in sympathetic activity induced by hypoxia is more pronounced in patients with hypertension compared to controls with normal BP [15].On the contrary, the deactivation of peripheral chemoreceptors during short-term hyperoxia resulted in reductions in both BP and MSNA in essential hypertension [14,16], confirming the contribution of peripheral chemoreflex to central sympathetic outflow, disease development, and progression.

Carotid body denervation in preclinical hypertension and metabolic disorders
Data from the rat model of neurogenic hypertension have demonstrated that CBD through carotid sinus nerve ablation reduces sympathetic activity, provides effective BP reduction, prevents diet-induced hypertension, and improves myocardial hypertrophy [17][18][19].In the mechanistic study of spontaneously hypertensive rats, CBD produced a rapid and substantial reduction in the renal sympathetic activity below preoperative baseline levels that was accompanied by a depressor response in hypertensive but not normotensive rats, in addition to improved cardiac baroreflex sensitivity, improved renal excretory function, reduced total proteinuria, and reduced T-cell infiltration into the aorta [17].Unilateral CBD, whether performed on the left or right side, was ineffective in lowering BP but subsequent resection of the contralateral (bilateral CBD) resulted in effective antihypertensive therapy.Another interesting finding is that CBD was associated with a greater reduction in BP compared to RDN, and combining both interventions produced a greater fall in systolic BP and sympathoinhibition that was similar in the total magnitude of BP reduction, independent of the order in which each procedure was performed, suggesting independent afferent inputs to disease process [17].
In addition to the role of the carotid body in the control of ventilation, findings in animal models suggest that the carotid body is a peripheral insulin sensor involved in the control of energy homeostasis [20].Animals exposed to hypercaloric diets exhibit carotid body activity contributing to insulin resistance and hypertension through augmented sympathetic activation [18].In support of this concept, further experimental studies have shown that selective bilateral resection of the carotid sinus nerve (CBD) completely prevents diet-induced insulin resistance, hyperglycaemia, dyslipidaemia, hypertension and sympathetic adrenal hyperactivity [18].These findings indicate that neuromodulation of carotid body activity is another potential therapeutic intervention for metabolic diseases, but human studies on disorders of glucose metabolism are lacking.

Carotid body removal for the treatment of asthma in human
Unilateral carotid body removal has been widely used for treating dyspnoea in bronchial asthma and chronic obstructive pulmonary disease (COPD) [21].In a total of 3900 patients with asthma who failed to respond to conventional therapy, carotid body removal resulted in a significant drop in BP within 6 months post-procedure, only in hypertensive patients in contrast to BP elevation in patients with hypotensive preoperative levels [22].The carotid body excision was described as having simple and often effective therapeutic effects in many cases with negligible residual symptoms and operative mortality [22].While the findings in patients with asthma and COPD appear promising, and the procedure proved safe, results regarding treatment efficacy have been inconclusive.Carotid body excision has been also routinely performed as a part of glomus tumour and unintentionally during carotid endarterectomies [23,24].

Carotid body removal in human-resistant hypertension
The association between potentiated tonic chemoreflex sensitivity and increased sympathetic activation in hypertension pathophysiology, and supportive results from pre-clinical and clinical studies, have encouraged the initiation of studies investigating the feasibility and efficacy of a therapeutic intervention for hypertension treatment directed at modulation of peripheral arterial chemoreceptors located in the carotid body.
The first prospective feasibility clinical trial evaluated the BP response to unilateral surgical carotid body excision in a total of 15 patients with resistant hypertension [25].On average, patients were taking 5.7 ± 0.6 (mean ± the standard error of the mean) antihypertensive drugs.In this study, patients underwent unilateral (4 on the left side/11 on the right side) carotid body removal, and the resection of glomus tissue was confirmed in 14 out of 15 patients.The remaining female patient, in whom no histopathological resection of the carotid body was confirmed, had no adverse events or changes in BP after the procedure.Unilateral carotid body removal on the right side resulted in reductions in daytime (-23 ± 3 mm Hg) and night-time (-20 ± 4 mm Hg) systolic BP at 3 months, in daytime (-26 ± 4 mm Hg) and night-time (-16 ± 5 mmHg) systolic BP at 6 months, and daytime (-12 ± 8 mm Hg) and night-time (-15 ± 6 mm Hg) systolic BP at 12 months follow-up.This BP-lowering effect was accompanied by a reduction in MSNA and improved baroreflex sensitivity in responders (8/15) but not in non-responders (6/15).In this study, a nonresponder was defined as having evidence of glomus cells in the resected tissue and BP reduction of less than 10 mm Hg in ambulatory BP at 3 months follow-up.In a patient previously treated with RDN and removal of the left carotid body, no short-term and long-term BP changes were noted post-procedure.The association between BP reduction and increased chemoreflex sensitivity suggests the underlying contributing mechanism of elevated BP in responders [25].There were two serious adverse events (i.e.prolonged hospitalisation of patients with difficult-to-control BP, one hospitalisation possibly related to the unilateral carotid body removal, the second hospitalisation unlikely to be related to the procedure) and an adverse event in a patient with pre-existing OSA whose apnoea-hypopnea index (AHI) increased from moderate to severe OSA at 3 months follow-up, and treatment with continuous positive airway pressure reduced the AHI.
Based on the study findings of surgical unilateral carotid body removal and resultant BP reduction, a further safety and feasibility study applied a radiofrequency catheter to selectively perform endovascular unilateral carotid body ablation in patients with resistant hypertension.Although the study was registered, no published data on arterial unilateral carotid body ablation are available.To minimise the potential risks of surgical excision of the carotid body, and an arterial-based ablation procedure (via femoral access), a transvenous ultrasound-based approach to carotid body ablation was developed and tested in a single-arm multicentre prospective study.Given the findings from previous studies of a lack of BP response after removal of the left carotid body, this study required confirmation of the anatomical presence of the carotid body at the bifurcation of the right common carotid artery as assessed by radiological imaging, as only the right-side carotid body was an inclusion criterion to be treated via venous access.So far, data were only presented as an abstract at the 2018 European Cardiology Meeting [26].In this study, 39 patients with resistant hypertension were enrolled, and 6 months follow-up data were available from 27 patients at the time of abstract submission.Patients were on an average of 4.5 ± 1.4 antihypertensive medications.At 6 months post-procedure, serious adverse events occurred including one transient ischaemic attack, one elective angiogram, one episode of hyperkalemia, one hypotensive episode, one episode of pneumonia, one groin closure complication, and one episode of chest pain.At 6 months follow-up, mean 24-hour ambulatory BP was reduced on average by 9.1 ± 13.5/6.7 ± 8.7 mm Hg from its baseline of mean systolic and diastolic BP of 154 ± 13/94 ± 13mm Hg, with similar reductions observed at 1 and 3 months follow-up.While preliminary data of carotid body modulation therapy are encouraging for treating hypertension in some individuals, it remains unclear if there is a dominant right carotid body for BP control or whether bilateral carotid body ablation in humans is safe and necessary to treat hypertension.There are currently no active, planned, or comparator clinical trials on the horizon that modulate the chemoreflex pathway.

Role of brain regions in sympathetic and blood pressure control
Tonic sympathetic activation and tonic arterial BP control depend on central integrative structures in the brain stem, the rostral ventrolateral medulla (RVLM) [3].Descending projections to the RVLM arise among others from the neurons in the peri-aqueductal grey and hypothalamic paraventricular nucleus (PVN).The RVLM integrates reflex neural mechanisms from arterial baroreceptors, chemoreceptors and various afferent sensory visceral receptors via direct connection with the upper part of the medulla through the NTS and PVN which modulate vasomotor sympathetic nerve discharge and BP.Under physiological conditions, arterial baroreceptors play a fundamental role in preventing excessive variability in BP.Afferent signals from baroreceptors stimulate the NTS in the upper part of the medulla in response to the distension of the vessel wall caused by transmural pressure.A signal arising from the NTS exerts a parasympathetic vagal effect resulting in slowing HR and reducing tonic sympathetic activity generated in the RVLM (Figure 2).

Baroreflex activation therapy in hypertension
The development of an implantable device to electrically or mechanically stimulate carotid sinus baroreceptors has provided a unique insight into human baroreflex physiology.Electric stimulation of each of the carotid sinus baroreceptors with the Rheos System (CVRx) has become an attractive approach for the treatment of uncontrolled hypertension.The Rheos device consists of bilateral electrodes and a pulse generator with programming accomplished with the use of an external system.The initial proof-of-concept multi-centre non-randomised trial (DEBuT-HT trial) included 45 high CVD risk patients with resistant hypertension.Mean office systolic and diastolic BP significantly decreased by 21/12 mm Hg 3 months following device implementation and was reduced by 33/22 mm Hg in patients (17/45) who completed two-year follow-up.Despite the safe and substantial BP-lowering effect, 8 patients experienced procedure-related serious adverse events [27].Following the DEBuT-HT trial, the safety and efficacy of BAT have been further determined in a multicentre double-blind randomised, placebo-controlled Rheos Pivotal Trial [28].A total of 265 patients with resistant hypertension were implanted and subsequently randomised (2:1) one month after BAT implantation, to Group A (device on) and Group B (device off) during the first 6 months period.This trial was specifically designed to assess five pre-specified coprimary endpoints, two for efficacy (acute and sustained BP reduction) and three for safety (procedural safety, BAT safety, and device safety).While the trial showed a significant benefit for sustained efficacy, BAT safety, and device safety, it did not meet the endpoints for acute responders or procedural safety.Office systolic BP decreased −16 ± 29 mm Hg (Group A) and −9 ± 29 mm Hg (Group B) at 6 months follow-up, and −25 ± 32 mm Hg (Group A, 12 months of BAT) and −25 ± 31 mm Hg (Group B, 6 months of BAT).At 12 months, 81% of patients experienced a drop in systolic BP of at least 10 mm Hg from pre-implant, and 63% of patients reached systolic BP of ≤140 mm Hg.There were in total 68 procedural events (surgical complication, nerve injury with the residual deficit, transient nerve injury, respiratory complication, wound complication), 16 hypertensive crises related to BAT safety (in both groups), and 6 strokes related to device safety.The limitations of the first-generation system associated with adverse events and the short-term battery life that limited its utility have been addressed with the implementation of the second Barostim neo device which consists of a unilateral electrode (sutured into the arterial wall to stimulate the carotid sinus), lead and an implantable pulse generator.In a single-arm open-label study, the Barostim neo system was implanted in 30 patients with resistant hypertension and activated 2 weeks after implan tation [29].From a preimplant baseline of 171.7 ± 20.2/99.5 ± 13.9 mm Hg (postimplant, preactivation BP of 160.6 ± 29.3/94.6 ± 19.0 mm Hg), office BP on average reduced by 26.1 ± 3.3 mm Hg, and remained stable at month 6, with an average systolic BP reduction of 26.0 ± 4.4 mm Hg.Furthermore, 43% of the resistant hypertensive patients achieved systolic BP <140 mm Hg by 6 months of therapy.BAT successfully reduced BP in six patients previously treated with RDN and was associated with fewer device-related side effects [29].Further findings were demonstrated in 28 patients who presented with elevated BP despite previous RDN performed at least 5 months before [30].There was a significant reduction in office systolic BP (-18 ± 28 mm Hg) at 6 months, and (-21 ± 26 mm Hg) at 12 months after BAT, in addition to reduced central systolic BP and reduced albuminuria.However, in patients with available 24-hour ambulatory BP monitoring, mean 24-hour systolic BP was unchanged (-2 ± 19 mm Hg) at 6 months, whereas a significant reduction (-14 ± 23 mm Hg) was observed at 12 months.
Within the treated patients with Barostim neo system, no device-related and procedure-related major adverse neurological and cardiovascular events occurred during the 6-month follow-up.There were reported minor side-effects (i.e.dysphonia, tingling, croakiness, dysphagia and hypotension), related to the intensity of therapy and were resolved consistently by adjustment of the device.Three patients developed temporary postoperative disturbance of wound healing or local infection [30].
The beneficial clinical utility of BAT was also reported in acute clinical scenarios.In general, the BAT device is activated approximately 2-4 weeks after surgical implantation to allow the site to heal, however, its immediate activation in a young male with hypertensive crisis following aortic dissection due to resistant hypertension that was unresponsive to sympatholytic agents, resulted in a rapid, significant and sustained reduction in BP out to 12 months post-procedure with no further incidence of hypertensive crisis [31].The long-term efficacy and safety of BAT are based on data available from the previous three trials of 383 patients with resistant hypertension [32].In this study, 143 patients completed 5 years of follow-up, and 48 patients completed 6 years of follow-up.In the entire cohort, office systolic BP fell from 179 ± 24 mm Hg to 144 ± 28 mm Hg, whereas office diastolic BP dropped from 103 ± 16 mm Hg to 85 ± 18 mm Hg.In this study, Authors took a closer look at the number of medications use, revealing a rather heterogeneous pattern.In 129 patients (27%), the number of medications fell from a median of 6 to a median of 3, in 129 patients (34%) medication use remained stable at a median of 5, and in 149 patients (39%) it increased from a median of 5 to a median of 7.An interesting relationship was found between the power of electric stimulation and medication use.In patients who required less medication, the power of stimulation was reduced over time, whereas the opposite pattern was observed in patients who progressively required more medication.Interestingly, patients with less medication and less stimulation power experienced a significantly lower BP compared to the remaining patients (139/82 versus 149/88 mm Hg; p < 0.01).The findings demonstrate that after 6 years of follow-up BAT maintains its efficacy for persistent reduction of office BP in patients with resistant hypertension without major safety issues.

Mechanical endovascular baroreflex amplification
An alternative therapeutic approach that modulates the autonomic nervous system is an endovascular device-based implant which increases wall strain and mechanically activates carotid baroreceptors.The MobiusHD (Vascular Dynamics, Mountain View, CA, USA) is delivered by a catheter via a femoral artery and is a nitinol self-expanding device implanted in the internal carotid artery to amplify the carotid baroreceptor signal.The safety and performance of the MobiusHD system were evaluated in the CALM-FIM_EUR prospective first-in-human study in 30 patients with resistant hypertension [33].Unilateral implantation of the MobiusHD device in the internal carotid artery decreased office BP from 184 ± 18 mm Hg for systolic and 109 ± 14 mm Hg for diastolic at baseline by 24/12 mm Hg at 6 months.The mean baseline 24 h ambulatory BP was 166/100 mm Hg (17/14) at baseline and was reduced by 21/12 mm Hg at 6 months for systolic and diastolic BP, resulting in less antihypertensive medication in most patients.The median number of antihypertensive medications was reduced by 0.50 and the median daily defined dose was reduced by 0.42 units at 6 months.Five serious adverse events (2 hypotension, worsening hypertension, intermittent claudication, and wound infection) occurred 6 months post-procedure.While endovascular baroreceptor amplification with the MobiusHD system substantially reduced BP with an acceptable safety profile, the currently ongoing CALM-2 randomised, double-blind, sham-controlled multicentre pivotal study evaluates the safety and effectiveness of this approach for the treatment of resistant hypertension.

Perspectives
Sympathetic nervous system activation is common in hypertension but the underlying neural mechanisms remain uncertain.Targeting neuroendocrine abnormalities is a major goal of hypertension management.Antihypertensive medicines are effective in improving BP control.However, medication non-adherence and physician inertia are major barriers to achieving BP treatment targets, importantly contributing to persistently low BP control rates [34].
The device-based therapies for treating hypertension have demonstrated sustained and durable BP reduction (out to one year with chemoreflex neuromodulation and out to 6 years with baroreflex neuromodulation).The successful response to device-based therapies does not depend on patient adherence, and patients following RDN therapy experience "always on" BP lowering effect throughout 24 h, including the high-risk morning surge [35].However, adherence to antihypertensive medication might be an important confounder in characterising the true effects of novel therapies on BP reduction.It seems that BAT makes the cardiovascular system more sensitive to the action of antihypertensive drugs.Nevertheless, evidence from the device-based therapies demonstrates that maintaining healthy lifestyle habits and antihypertensive medicines are still necessary to adequately manage hypertension after the intervention.
Notably, BP response to available device-based therapies is variable and cannot be predicted before the procedure.When sympathetic activation is present in hypertension it is differentiated, not necessarily involving all sympathetic outflows [5], thereby testing the completeness of device-based therapies (i.e. chemoreflex neuromodulation, baroreflex neuromodulation, or RDN) in human studies is challenging.There is no easily accessible sympathetic validated biomarker that determines which candidate benefits and from which procedure.Several aspects including comprehensive patient assessment and selection, exclusion of secondary hypertension, and pseudo-resistance need to be appropriately addressed before considering the device-based treatment.
The positive results from carotid-based therapies including carotid body modulation and BAT with the Barostim neo or endovascular MobiusHD systems appear promising, but rather as an adjunctive to antihypertensive medication treatment modality for patients with resistant hypertension.While the procedures are feasible, they should be performed in carefully selected patients by experienced operators in endovascular carotid artery intervention, considering the potentially device-related safety adverse events.More evidence from randomised sham-controlled studies regarding the safety and treatment efficacy is needed before chemoreflex and baroreflex neuromodulation therapy can be implemented in clinical practice.

Figure 1 .
Figure 1.Carotid sinus and carotid body.The carotid sinus nerve (a branch of the glossopharyngeal nerve, cranial nerve IX) contains afferent fibres from arterial chemoreceptors in the carotid body and arterial baroreceptors in the carotid sinus.The carotid sinus wall contains arterial baroreceptors sensitive to blood pressure (BP) changes.Baroreflex neuromodulation with baroreflex activation therapy aims to stimulate baroreceptors in the carotid sinus to treat hypertension.Carotid body is located near the carotid sinus at the bifurcation of the common carotid artery and is the main peripheral arterial chemoreceptor, sensitive primarily to hypoxia (reduced o 2 level).Chemoreflex neuromodulation with unilateral carotid body removal or carotid body denervation aims to eliminate inputs from the carotid body to treat hypertension.

Figure 2 .
Figure 2.In response to elevated blood pressure (BP) afferent nerve fibres (carotid sinus nerve) from arterial baroreceptors pass the signal to the nucleus tractus solitarius (NTs) in the dorsal medulla in the brain stem, resulting in reduced heart rate (through the vagus nerve) and tonic sympathetic activity generated in the brain stem.In response to hypoxia, afferent nerve fibres from peripheral arterial chemoreceptors pass the signal to the NTs, leading to simultaneous hyperventilation and selective vasoconstriction (sympathetic activation), whereas hyperventilation inhibits autonomic response to hypoxaemia causing bradycardia (through the vagus nerve).