Electrostimulation of the carotid sinus nerve in mice attenuates inflammation via glucocorticoid receptor on myeloid immune cells.

BACKGROUND: The carotid bodies and baroreceptors are sensors capable of detecting various physiological parameters that signal to the brain via the afferent carotid sinus nerve for physiological adjustment by efferent pathways. Because receptors for inflammatory mediators are expressed by these sensors, we and others have hypothesised they could detect changes in pro-inflammatory cytokine blood levels and eventually trigger an anti-inflammatory reflex. METHODS: To test this hypothesis, we surgically isolated the carotid sinus nerve and implanted an electrode, which could deliver an electrical stimulation package prior and following a lipopolysaccharide injection. Subsequently, 90 min later, blood was extracted, and cytokine levels were analysed. RESULTS: Here, we found that carotid sinus nerve electrical stimulation inhibited lipopolysaccharide-induced tumour necrosis factor production in both anaesthetised and non-anaesthetised conscious mice. The anti-inflammatory effect of carotid sinus nerve electrical stimulation was so potent that it protected conscious mice from endotoxaemic shock-induced death. In contrast to the mechanisms underlying the well-described vagal anti-inflammatory reflex, this phenomenon does not depend on signalling through the autonomic nervous system. Rather, the inhibition of lipopolysaccharide-induced tumour necrosis factor production by carotid sinus nerve electrical stimulation is abolished by surgical removal of the adrenal glands, by treatment with the glucocorticoid receptor antagonist mifepristone or by genetic inactivation of the glucocorticoid gene in myeloid cells. Further, carotid sinus nerve electrical stimulation increases the spontaneous discharge activity of the hypothalamic paraventricular nucleus leading to enhanced production of corticosterone. CONCLUSION: Carotid sinus nerve electrostimulation attenuates inflammation and protects against lipopolysaccharide-induced endotoxaemic shock via increased corticosterone acting on the glucocorticoid receptor of myeloid immune cells. These results provide a rationale for the use of carotid sinus nerve electrostimulation as a therapeutic approach for immune-mediated inflammatory diseases.

Magnetic stimulation of carotid sinus as a treatment for hypertension.

Previously, we reported that magnetic stimulation of carotid sinus (MSCS) could lower arterial pressure in rabbits. In this randomized, sham-controlled pilot study, we evaluated the effects of MSCS on blood pressure in pre-hypertensive and hypertensive subjects. A total of 15 subjects with blood pressure higher than 130/80 mm Hg were randomized to receive sham or 1Hz MSCS. The changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MAP) during treatment were compared between groups. The heart rate variability (HRV) and baroreflex sensitivity (BRS) before, during, and after treatments were analyzed. Reduction of SBP was significantly greater in subjects with MSCS than those with sham stimulation (6.6 ± 0.4 vs -2.5 ± 0.4 mm Hg, P < 0.001). Reduction of DBP was significantly greater in subjects with MSCS than those with sham stimulation (1.2 ± 0.2 vs -2.8 ± 0.2 mm Hg, P < 0.001). Reduction of MAP was significantly greater in subjects with MSCS than those with sham stimulation (1.4 ± 0.3 mm Hg vs -4.0 ± 0.3 mm Hg, P < 0.001). Reduction of HR was significantly greater in subjects with MSCS than those with sham stimulation (0.5 ± 0.5 vs -1.9 ± 0.3 beats/min, P = 0.002). BRS increased from 6.85 ± 0.77 to 8.79 ± 0.95 ms/mm Hg after MSCS compared with that at baseline (P = 0.027). Thus, MSCS can lower blood pressure and heart rate in pre-hypertensive and hypertensive subject, warranting further study for establishing MSCS as a treatment for hypertension.

Effects of the Right Carotid Sinus Compression Technique on Blood Pressure and Heart Rate in Medicated Patients with Hypertension.

OBJECTIVES: To identify the immediate and middle-term effects of the right carotid sinus compression technique on blood pressure and heart rate in hypertensive patients. DESIGN: Randomized blinded experimental study. SETTINGS: Primary health centers of Cáceres (Spain). SUBJECTS: Sixty-four medicated patients with hypertension were randomly assigned to an intervention group (n = 33) or to a control group (n = 31). INTERVENTION: In the intervention group a compression of the right carotid sinus was applied for 20 sec. In the control group, a placebo technique of placing hands on the radial styloid processes was performed. OUTCOME MEASURES: Blood pressure and heart rate were measured in both groups before the intervention (preintervention), immediately after the intervention, 5 min after the intervention, and 60 min after the intervention. RESULTS: The intervention group significantly decreased systolic and diastolic blood pressure and heart rate immediately after the intervention, with a large clinical effect; systolic blood pressure remained reduced 5 min after the intervention, and heart rate remained reduced 60 min after the intervention. No significant changes were observed in the control group. CONCLUSIONS: Right carotid sinus compression could be clinically useful for regulating acute hypertension.

Carotid sinus hypersensitivity: block of the sternocleidomastoid muscle does not affect responses to carotid sinus massage in healthy young adults.

The arterial baroreflex is crucial for short-term blood pressure control - abnormal baroreflex function predisposes to syncope and falling. Hypersensitive responses to carotid baroreflex stimulation using carotid sinus massage (CSM) are common in older adults and may be associated with syncope. The pathophysiology of this hypersensitivity is unknown, but chronic denervation of the sternocleidomastoid muscles is common in elderly patients with carotid sinus hypersensitivity (CSH), and is proposed to interfere with normal integration of afferent firing from the carotid baroreceptors with proprioceptive feedback from the sternocleidomastoids, producing large responses to CSM. We hypothesized that simulation of sternocleidomastoid "denervation" using pharmacological blockade would increase cardiovascular responses to CSM. Thirteen participants received supine and tilted CSM prior to intramuscular injections (6-8 mL distributed over four sites) of 2% lidocaine hydrochloride, and 0.9% saline (placebo) in contralateral sternocleidomastoid muscles. Muscle activation was recorded with electromyography (EMG) during maximal unilateral sternocleidomastoid contraction both pre- and postinjection. Supine and tilted CSM were repeated following injections and responses compared to preinjection. Following lidocaine injection, the muscle activation fell to 23 ± 0.04% of the preinjection value (P < 0.001), confirming neural block of the sternocleidomastoid muscles. Cardiac (RRI, RR interval), forearm vascular resistance (FVR), and systolic arterial pressure (SAP) responses to CSM did not increase after lidocaine injection in either supine or tilted positions (supine: ΔRRI -72 ± 31 ms, ΔSAP +2 ± 1 mmHg, ΔFVR +4 ± 4%; tilted: ΔRRI -20 ± 13 ms, ΔSAP +2 ± 2 mmHg, ΔFVR +2 ± 4%; all P > 0.05). Neural block of the sternocleidomastoid muscles does not increase cardiovascular responses to CSM. The pathophysiology of CSH remains unknown.

Carotid sinus nerve electrical stimulation in conscious rats attenuates systemic inflammation via chemoreceptor activation.

Recent studies demonstrated a critical functional connection between the autonomic (sympathetic and parasympathetic) nervous and the immune systems. The carotid sinus nerve (CSN) conveys electrical signals from the chemoreceptors of the carotid bifurcation to the central nervous system where the stimuli are processed to activate sympathetic and parasympathetic efferent signals. Here, we reported that chemoreflex activation via electrical CSN stimulation, in conscious rats, controls the innate immune response to lipopolysaccharide attenuating the plasma levels of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6). By contrast, the chemoreflex stimulation increases the plasma levels of anti-inflammatory cytokine interleukin 10 (IL-10). This chemoreflex anti-inflammatory network was abrogated by carotid chemoreceptor denervation and by pharmacological blockade of either sympathetic - propranolol - or parasympathetic - methylatropine - signals. The chemoreflex stimulation as well as the surgical and pharmacological procedures were confirmed by real-time recording of hemodynamic parameters [pulsatile arterial pressure (PAP) and heart rate (HR)]. These results reveal, in conscious animals, a novel mechanism of neuromodulation mediated by the carotid chemoreceptors and involving both the sympathetic and parasympathetic systems.

Rescue baroreflex activation therapy after Stanford B aortic dissection due to therapy-refractory hypertension.

Clinical trials have demonstrated significant and durable reduction in arterial pressure from baroreflex activation therapy (BAT) in patients with resistant arterial hypertension. There is a lack of data, however, concerning the use of BAT in a rescue approach during therapy-refractory hypertensive crisis resulting in life-threatening end-organ damage. Here, we describe the first case in which BAT was applied as a rescue procedure in an intensive care setting after ineffective maximum medical treatment. A 34-year-old male patient presented with Stanford B aortic dissection and hypertensive crisis. The dissection membrane extended from the left subclavian artery down to the right common iliac artery, resulting in a total arterial occlusion of the right leg. After emergency thoracic endovascular aortic repair and femorofemoral crossover bypass, the patient developed a compartment syndrome of the right lower limb, ultimately leading to amputation of the right leg above the knee. Even under deep sedation recurrent hypertensive crises of up to 220 mm Hg occurred that could not be controlled by eight antihypertensive drugs of different classes. Screening for secondary hypertension was negative. Eventually, rescue implantation of right-sided BAT was performed as a bailout procedure, followed by immediate activation of the device. After a hospital stay of a total of 8 weeks, the patient was discharged 2 weeks after BAT initiation with satisfactory blood pressure levels. After 1-year follow-up, the patient has not had a hypertensive crisis since the onset of BAT and is currently on fourfold oral antihypertensive therapy. The previously described bailout procedures for the treatment of life-threatening hypertensive conditions that are refractory to drug treatment have mainly comprised the interventional denervation of renal arteries. The utilization of BAT is new in this emergency context and showed a significant, immediate, and sustained reduction of blood pressure levels after activation. To our knowledge, we report the first case of an immediate activation of a barostim while the device is usually not activated before 2 to 4 weeks after implantation to allow time for the surgical site to heal. During the follow-up period, the healing process was not impaired, and a significant, immediate, and sustained reduction of blood pressure levels after activation could be observed. This treatment option offers maximum adherence to antihypertensive therapy to avoid future cardiovascular end-organ damage and possibly reduce antihypertensive medication and undesirable side effects.

Baroreflex Activation Therapy in Heart Failure With Reduced Ejection Fraction: Available Data and Future Perspective.

Progression of heart failure with reduced ejection fraction (HFrEF) is promoted by sympathovagal imbalance. Baroreflex activation therapy, i.e., electrical stimulation of baroreceptors at the carotid sinus, can restore sympathovagal balance. Large animal studies of baroreflex activation therapy revealed improvements in cardiac function, susceptibility to ventricular arrhythmias, and a survival benefit as compared to untreated controls. Recently, the first randomized and controlled trial of optimal medical and device therapy alone or plus baroreflex activation therapy in patients suffering from HFrEF was published. It demonstrated a reasonable safety profile in this severely ill patient population. Moreover, the study found significant improvements in New York Heart Association class, quality of life, 6-min walk distance, and NT-proBNP levels. This review provides an overview on baroreflex activation therapy for the treatment of HFrEF-from the concept and preclinical findings to most recent clinical data and upcoming trials.

Baroreflex activation therapy in the treatment of resistant hypertension.

Baroreceptors are sensory nerve endings in the carotid sinuses and the aortic arch. Notably, a dysfunction in the autonomic nervous system (sympathetic hyperactivity) has been shown to be part of the pathophysiology of chronic hypertension. Baroreflex activation therapy is an invasive treatment modality to decrease blood pressure by stimulating baroreceptors in the wall of the carotid sinus. Preliminary results of baroreflex activation therapy in resistant hypertension and systolic heart failure have been promising. If its effect can be proven in controlled studies, it may serve as an important new tool in the treatment of patients with resistant hypertension at a high risk of cardiovascular complications.

Carotid Sinus/Nerve Stimulation for Treatment of Resistant Hypertension and Heart Failure.

Hypertension and cardiovascular disease are leading causes of morbidity and mortality worldwide. The prevalence of resistant hypertension remains high and is expected to increase. Moreover, there are limitations to therapeutic interventions aimed at treating resistant hypertension and heart failure despite the wide availability of therapeutic agents and dietary and lifestyle modification. Device-based therapy by baroreflex activation via carotid sinus/nerve stimulation is currently undergoing investigation, and promising findings from clinical trials have been published. Baroreflex activation therapy may represent a new approach for treatment of these conditions by reducing sympathetic drive and increasing parasympathetic activity. Here we describe a new technology which is designed to deliver carotid sinus stimulation to electrically activate the carotid baroreceptors and baroreflex, thereby reducing blood pressure and improving cardiac function. The theory, surgical techniques, and clinical trials of carotid sinus stimulation are highlighted.

Vagal stimulation by manual carotid sinus massage to acutely suppress seizures.

Carotid sinus massage, a technique involving digital pressure on the richly innervated carotid sinus, is a time-honoured method for termination of supraventricular tachycardia due to paroxysmal atrial tachycardia. Vagal nerve stimulation, a more recent technique, employs pacemaker stimulation of the vagus as a treatment for refractory epilepsy. This case report discusses the use of carotid sinus massage to abort seizure activity. The patient used manual manipulation of the carotid sinus (similar to cardiology techniques) to suppress seizures, achieving a therapeutic neurological outcome.

Effects of L-type Ca2+ channel blocker nifedipine on dynamic arterial blood pressure control.

Dynamic characteristics of arterial pressure (AP) regulation are important components in our understanding of rapid AP restoration by the arterial baroreflex system. The present study examined the effects of an L-type Ca(2+) channel blocker nifedipine on baroreflex-mediated dynamic AP regulation. In anesthetized and vagotomized rats, carotid sinus pressure was externally perturbed using a Gaussian white noise signal, and the neural arc transfer function from pressure input to efferent sympathetic nerve activity (SNA) and the peripheral arc transfer function from SNA to AP were identified. The peripheral arc transfer function approximated a second-order low-pass filter with pure dead time. Intravenous administration of nifedipine significantly decreased the steady-state gain and increased the damping ratio of the peripheral arc without affecting the dynamic characteristics of the neural arc. When the step response of AP was calculated based on the peripheral arc transfer function alone, nifedipine prolonged 80% rise time by 26%. When the closed-loop AP response was simulated based on both the neural arc and peripheral arc transfer functions and the dynamic gain of the baroreflex total loop was assumed to be 2.0, nifedipine prolonged 80% recovery time by 107%. In conclusion, L-type Ca(2+) channel blockade may compromise the baroreflex-mediated AP control not only in the magnitude but also in the speed of AP restoration.

Carotid sinus syndrome.

Carotid sinus hypersensitivity was first reported more than 200 years ago. Nevertheless, a complete understanding of this relatively common clinical finding in older patients has proven elusive. There is evidence to support an association between symptoms, particularly syncope, and a hypersensitive response to carotid sinus massage. However, the clinical implication of a high prevalence in asymptomatic healthy older persons is not known. A central degenerative process likely underlies the pathophysiology, but this is as yet unproven. Although selected patients have had symptom improvement with treatment, particularly permanent pacing, there is a dearth of randomized controlled trial data to guide management.

Bionic baroreceptor corrects postural hypotension in rats with impaired baroreceptor.

BACKGROUND: Impairment of the arterial baroreflex causes orthostatic hypotension. Arterial baroreceptor sensitivity degrades with age. Thus, an impaired baroreceptor plays a pivotal role in orthostatic hypotension in most elderly patients. There is no effective treatment for orthostatic hypotension. The aims of this investigation were to develop a bionic baroreceptor (BBR) and to verify whether it corrects postural hypotension. METHODS AND RESULTS: The BBR consists of a pressure sensor, a regulator, and a neurostimulator. In 35 Sprague-Dawley rats, we vascularly and neurally isolated the baroreceptor regions and attached electrodes to the aortic depressor nerve for stimulation. To mimic impaired baroreceptors, we maintained intracarotid sinus pressure at 60 mm Hg during activation of the BBR. Native baroreflex was reproduced by matching intracarotid sinus pressure to the instantaneous pulsatile aortic pressure. The encoding rule for translating intracarotid sinus pressure into stimulation of the aortic depressor nerve was identified by a white noise technique and applied to the regulator. The open-loop arterial pressure response to intracarotid sinus pressure (n=7) and upright tilt-induced changes in arterial pressure (n=7) were compared between native baroreceptor and BBR conditions. The intracarotid sinus pressure-arterial pressure relationships were comparable. Compared with the absence of baroreflex, the BBR corrected tilt-induced hypotension as effectively as under native baroreceptor conditions (native, -39±5 mm Hg; BBR, -41±5 mm Hg; absence, -63±5 mm Hg; P<0.05). CONCLUSIONS: The BBR restores the pressure buffering function. Although this research demonstrated feasibility of the BBR, further research is needed to verify its long-term effect and safety in larger animal models and humans.

Anesthetic management for implantation of a treatment device: the Rheos Baroreflex Hypertensive Therapy System.

Resistant hypertension is a prevalent dilemma. Despite all available antihypertensive medications and multiple strategies such as healthier diets and exercise programs, many patients are still unable to maintain or reach a therapeutic goal for systolic blood pressure. Because of this major health concern, CVRx, Inc has developed a treatment involving baroreflex activation therapy (Rheos Baroreflex Hypertension Therapy System) to treat patients with uncontrolled high blood pressure. The surgical implantation of this system is similar to a carotid endarterectomy procedure; however, the anesthetic management for this procedure is unique and challenging. This case report describes a 45-year-old African American woman with a history of hypertension who was receiving multiple antihypertensive medications and, thus, was a qualified candidate for implantation of this device. The goal of anesthetic management during implantation of this hypertension therapy system is to preserve the carotid sinus baroreceptor sensitivity by avoiding administering anesthetic agents that inhibit the baroreceptor reflex during electrode placement and the testing period. Because of the restriction of some of the anesthetic agents that an anesthesia provider can use, this procedure poses major challenges to the anesthesia provider in planning for anesthesia care and managing risks to the patient.

Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial.

The objective of this study was to assess long-term blood pressure control in resistant hypertension patients receiving baroreflex activation therapy (BAT). Following completion of the randomized Rheos Pivotal Trial, patients participated in open-label, nonrandomized follow-up to assess safety and efficacy of BAT. Blood pressure reductions were measured relative to a pre-implant baseline as well as the results achieved at the completion of 1 year of follow-up in the randomized phase. Clinically significant responder status was assessed according to FDA-mandated criteria. Of the 322 patients implanted, 76% (n = 245) qualified as clinically significant responders, an additional 10% were indeterminate. Among long-term responders receiving BAT, the mean blood pressure drop was 35/16 mm Hg. Medication use was reduced by the end of the randomized phase and remained lower through the follow-up period. Among responders, 55% achieved goal blood pressures (<140 mm Hg or <130 mm Hg in diabetes or kidney disease). Blood pressures of all active patients remained stable from completion of the randomized phase through long-term follow-up. BAT substantially reduced arterial pressure for most patients participating in the Rheos Pivotal Trial. This blood pressure reduction or goal achievement was maintained over long-term follow-up of 22 to 53 months.

Arterial stiffness and the response to carotid sinus massage in older adults.

BACKGROUND AND AIMS: Carotid sinus hypersensitivity (CSH) is a common cause of fainting and falls in the older adult population and is diagnosed by carotid sinus massage (CSM). Previous work has suggested that age-related stiffening of blood vessels reduces afferent input from the carotid sinus leading to central upregulation of the overall arterial baroreflex response. We examined the differences in arterial stiffness and baroreflex function in older adults at high cardiovascular risk (advanced age, Type 2 diabetes, hypertension and hyperlipidemia) with and without CSH. METHODS: Forty-three older adults (mean age 71.4+/-0.7) with Type 2 diabetes, hyperlipidemia and hypertension were recruited. After resting supine for 45 minutes prior to the start of data collection, each subject had arterial stiffness measured by pulse wave velocity (PWV, Complior SD), followed by spontaneous baroreflex measures (Baroreflex sensitivity, BRS) and CSM. RESULTS: Of the 43 subjects tested, 10 subjects met the criteria for CSH (8 pure vasodepressor and 2 mixed CSH). CSH subjects had higher measures of arterial stiffness when compared to normal subjects for both radial PWV (11.5+/-0.6 vs 9.6+/-0.4 m/s, p=0.043) and femoral PWV (13.4+/-0.9 vs 11.0+/-0.5 m/s, p=0.036). The CSH group demonstrated significantly lower BRS as compared to the normal group (BRS, 6.73+/-0.58 vs 10.41+/-0.85 ms/mmHg, p=0.038). These results were unchanged when the analysis was repeated with only the VD subjects. CONCLUSIONS: Older adults with CSH have higher arterial stiffness and reduced arterial baroreflex sensitivity. There was no evidence to support upregulation of the arterial baroreflex in patients with CSH.