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.

Carotid sinus nerve stimulation attenuates alveolar bone loss and inflammation in experimental periodontitis.

Baroreceptor and chemoreceptor reflexes modulate inflammatory responses. However, whether these reflexes attenuate periodontal diseases has been poorly examined. Thus, the present study determined the effects of electrical activation of the carotid sinus nerve (CSN) in rats with periodontitis. We hypothesized that activation of the baro and chemoreflexes attenuates alveolar bone loss and the associated inflammatory processes. Electrodes were implanted around the CSN, and bilateral ligation of the first mandibular molar was performed to, respectively, stimulate the CNS and induce periodontitis. The CSN was stimulated daily for 10 min, during nine days, in unanesthetized animals. On the eighth day, a catheter was inserted into the left femoral artery and, in the next day, the arterial pressure was recorded. Effectiveness of the CNS electrical stimulation was confirmed by hypotensive responses, which was followed by the collection of a blood sample, gingival tissue, and jaw. Long-term (9 days) electrical stimulation of the CSN attenuated bone loss and the histological damage around the first molar. In addition, the CSN stimulation also reduced the gingival and plasma pro-inflammatory cytokines induced by periodontitis. Thus, CSN stimulation has a protective effect on the development of periodontal disease mitigating alveolar bone loss and inflammatory processes.

Carotid baroreceptor stimulation in obese rats affects white and brown adipose tissues differently in metabolic protection.

The sympathetic nervous system (SNS) regulates the functions of white adipose tissue (WAT) and brown adipose tissue (BAT) tightly. Carotid baroreceptor stimulation (CBS) efficiently inhibits SNS activation. We hypothesized that CBS would protect against obesity. We administered CBS to obese rats and measured sympathetic and AMP-activated protein kinase (AMPK)/ PPAR pathway responses as well as changes in perirenal WAT (PWAT), epididymal WAT (EWAT), and interscapular BAT (IBAT). CBS alleviated obesity-related metabolic changes, improving insulin resistance; reducing adipocyte hypertrophy, body weight, and adipose tissue weights; and decreasing norepinephrine but increasing acetylcholine in plasma, PWAT, EWAT, and IBAT. CBS also downregulated fatty acid translocase (CD36), fatty acid transport protein (FATP), phosphorylated and total hormone sensitive lipase, phosphorylated and total protein kinase A, and PPARγ in obese rats. Simultaneously, CBS upregulated phosphorylated adipose triglyceride lipase, phosphorylated and total AMPK, and PPARα in PWAT, EWAT, and IBAT. However, BAT and WAT responses differed; although many responses were more sensitive in IBAT, responses of CD36, FATP, and PPARγ were more sensitive in PWAT and EWAT. Overall, CBS decreased chronically activated SNS and ameliorated obesity-related metabolic disorders by regulating the AMPK/PPARα/γ pathway.

Tonic aortic depressor nerve stimulation does not impede baroreflex dynamic characteristics concomitantly mediated by the stimulated nerve.

Although electrical activation of the carotid sinus baroreflex (baroreflex activation therapy) is being explored as a device therapy for resistant hypertension, possible effects on baroreflex dynamic characteristics of interaction between electrical stimulation and pressure inputs are not fully elucidated. To examine whether the electrical stimulation of the baroreceptor afferent nerve impedes normal short-term arterial pressure (AP) regulation mediated by the stimulated nerve, we electrically stimulated the right aortic depressor nerve (ADN) while estimating the baroreflex dynamic characteristics by imposing pressure inputs to the isolated baroreceptor region of the right ADN in nine anesthetized rats. A Gaussian white noise signal with a mean of 120 mmHg and standard deviation of 20 mmHg was used for the pressure perturbation. A tonic ADN stimulation (2 or 5 Hz, 10 V, 0.1-ms pulse width) decreased mean sympathetic nerve activity (367.0 ± 70.9 vs. 247.3 ± 47.2 arbitrary units, P < 0.01) and mean AP (98.4 ± 7.8 vs. 89.2 ± 4.5 mmHg, P < 0.01) during dynamic pressure perturbation. The ADN stimulation did not affect the slope of dynamic gain in the neural arc transfer function from pressure perturbation to sympathetic nerve activity (16.9 ± 1.0 vs. 14.7 ± 1.6 dB/decade, not significant). These results indicate that electrical stimulation of the baroreceptor afferent nerve does not significantly impede the dynamic characteristics of the arterial baroreflex concomitantly mediated by the stimulated nerve. Short-term AP regulation by the arterial baroreflex may be preserved during the baroreflex activation therapy.

Effects of chronic carotid baroreceptor activation on arterial stiffness in severe heart failure.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is characterized by activation of the sympathetic nervous system and increased arterial stiffness, leading to an impaired ventricular-vascular coupling. Baroreflex activation therapy (BAT) has been shown to reduce muscle sympathetic nerve activity (MSNA) and improve clinical status of patients with HFrEF. The purpose of this investigation was to determine the effects of BAT on arterial stiffness in HFrEF. METHODS AND RESULTS: MSNA, clinical variables, and parameters of central blood pressure (BP) and arterial stiffness were collected in 18 NYHA Class III HFrEF patients, nine receiving BAT and nine continuing with optimal medical management alone. Patients were followed for 3 months, with measurements at that time compared to baseline evaluation. Baseline characteristics of the groups were well matched. At 3 months, BAT did not improve central BP and arterial stiffness despite a significant amelioration of MSNA, NYHA class, Minnesota living with heart failure questionnaire score, number of heart failure medications and six-minute walking distance. The control group exhibited no significant changes in all the measured variables. CONCLUSIONS: Despite significant reductions in MSNA and clinical improvement, BAT does not appear to chronically modify arterial stiffness within this HFrEF cohort. Additional study is required to determine if this result applies to the HFrEF population as a whole.

Surgical Experience and Long-term Results of Baroreflex Activation Therapy for Heart Failure With Reduced Ejection Fraction.

The purpose of this publication is to describe the intraoperative experience along with long-term safety and efficacy of the second-generation baroreflex activation therapy (BAT) system in patients with heart failure (HF) and reduced ejection fraction HF (HFrEF). In a randomized trial of New York Heart Association Class III HFrEF, 140 patients were assigned 1:1 to receive BAT plus medical therapy or medical therapy alone. Procedural information along with safety and efficacy data were collected and analyzed over 12 months. Within the cohort of 71 patients randomized to BAT, implant procedure time decreased with experience, from 106 ± 37 minutes on the first case to 83 ± 32 minutes on the third case. The rate of freedom from system- and procedure-related complications was 86% through 12 months, with the percentage of days alive without a complication related to system, procedure, or underlying cardiovascular condition identical to the control group. The complications that did occur were generally mild and short-lived. Overall, 12 months therapeutic benefit from BAT was consistent with previously reported efficacy through 6 months: there was a significant and sustained beneficial treatment effect on New York Heart Association functional Class, quality of life, 6-minute hall walk distance, plasma N-terminal pro-brain natriuretic peptide, and systolic blood pressure. This was true for the full trial cohort and a predefined subset not receiving cardiac resynchronization therapy. There is a rapid learning curve for the specialized procedures entailed in a BAT system implant. BAT system implantation is safe with the therapeutic benefits of BAT in patients with HFrEF being substantial and maintained for at least 1 year.

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.

Novel Interventional Therapies to Modulate the Autonomic Tone in Heart Failure.

Heart failure (HF) represents a significant and expanding public health burden associated with increasing prevalence and exponential growth in related health care costs. Contemporary advances in both pharmacological and nonpharmacological therapies have often been restricted in application and benefit. Given the critical role of the autonomic nervous system (ANS) in maintaining cardiovascular homeostasis in the failing heart, there has been increasing interest in the role of ANS modulation as a therapeutic modality in HF. In this review, we highlight the anatomy of the ANS and its role in the pathophysiology of HF, as well as metrics of its assessment. Given the limitations associated with pharmacological ANS modulation, including lack of specificity and medication intolerance, we focus in this review on contemporary nonpharmacological ANS modulation therapies. For each therapy-vagal nerve stimulation, carotid baroreceptor stimulation, spinal cord stimulation, and renal denervation-we review the rationale for modulation, pre-clinical and clinical assessments, as well as procedural considerations and limitations. We conclude by commenting on novel technologies and strategies for ANS modulation on the horizon.

Initial experience with therapeutic geometric modification of the carotid bulb for true resistant hypertension.

The contribution of carotid baroreceptor feedback in preventing or potentially contributing to the essential hypertensive cascade is poorly understood. It is clear the carotid sinus nerve action potentials are triggered by carotid bulb stretch rather than pressure and are only sustained during pulsatile increases in pressure. In addition, the carotid baroreceptor negative feedback is gradually extinguished in hypertension patients (a phenomenon known as "resetting"). We report a case of significant reduction in blood pressure in a patient with true resistant hypertension after change in the carotid bulb pulsatile strain patterns following the implant of an intravascular prosthesis.

Electrical carotid baroreceptor stimulation.

The Barostim neo ™ system is a novel implantable device that activates the carotid baroreflex. It decreases the sympathetic activity and inhibits the renin system, which results in reduced blood pressure and heart rate. In patients with resistant hypertension, electrically activation of the baroreflex leads to an average decrease in systolic blood pressure of 38, 36, 40 and 53 mmHg at 1, 2, 3 and 4 years, respectively. Additionally, cardiac remodelling with reduced left ventricular mass and posterior wall thickness has been observed in long-term studies. In a limited number of patients with heart failure, baroreflex activation therapy leads to a decrease in muscle sympathetic nerve activity and to improved quality of life and functional capacities. The implantation procedure is safe and associated with risks comparable with those of other active implantable devices. Barostim neo is currently available in several European countries.

Baroreflex activation therapy for patients with drug-resistant hypertension.

Uncontrolled or resistant hypertension is still a major problem facing many physicians daily in the clinic. Several new therapies are being developed to help those patients whose blood pressure does not respond sufficiently to regular antihypertensive medication. One of these promising therapies is electrical activation of the carotid sinus baroreflex. In this overview, the authors predominantly summarize the background, efficacy and safety of this promising treatment with its latest achievements in patients with resistant hypertension. The authors also discuss certain issues that need further clarification before this therapy can be added to the common treatment guidelines of hypertension.

Non-pharmacological modulation of the autonomic tone to treat heart failure.

The autonomic nervous system has a significant role in the pathophysiology and progression of heart failure. The absence of any recent breakthrough advances in the medical therapy of heart failure has led to the evolution of innovative non-pharmacological interventions that can favourably modulate the cardiac autonomic tone. Several new therapeutic modalities that may act at different levels of the autonomic nervous system are being investigated for their role in the treatment of heart failure. The current review examines the role of renal denervation, vagal nerve stimulators, carotid baroreceptors, and spinal cord stimulators in the treatment of heart failure.

Research needs in the area of device-related treatments for hypertension.

Hypertension is the primary risk factor for cardiovascular and renal-disease endpoints. Medications help many patients but not all. Recently, two device-related treatments have been introduced, catheter-based renal denervation and electrical carotid sinus stimulation. Remuneration for these treatments is guaranteed in many countries even though basic information is missing. We draw attention to deficiencies in the database. For catheter-based renal denervation, few large-animal data are available to investigate the effect of the intervention on the histology of the arterial wall. No functional data are available regarding re-innervation. For carotid sinus stimulation, the situation is similar. Acute activation of either treatment seems to reduce sympathetic tone dramatically. However, whether or not the effects are sustained over time is unknown. No 'end-point' data are available for either treatment. Devices should be subjected to evidence-based standards before widespread introduction.

Resistant hypertension: the role of interventional therapy.

Resistant hypertension still represents a major health problem, incompletely resolved by the current therapeutic interventions. Based on the interference of sympathetic over activity in resistant hypertension, novel invasive strategies such as sympathetic renal denervation and carotid baroreceptor stimulation have recently emerged. Despite the promising results and their good tolerability profile, the optimal role of these non-pharmacologic therapies relative to conventional medical regimens, remains unknown. Further investigation is also necessary to establish their real long-term efficacy and safety in clinical practice.

Electrical carotid sinus stimulation in treatment resistant arterial hypertension.

Treatment resistant arterial hypertension is commonly defined as blood pressure that remains above goal in spite of the concurrent use of three antihypertensive agents of different classes. The sympathetic nervous system promotes arterial hypertension and cardiovascular as well as renal damage, thus, providing a logical treatment target in these patients. Recent physiological studies suggest that baroreflex mechanisms contribute to long-term control of sympathetic activity and blood pressure providing an impetus for the development of electrical carotid sinus stimulators. The concept behind electrical stimulation of baroreceptors or baroreflex afferent nerves is that the stimulus is sensed by the brain as blood pressure increase. Then, baroreflex efferent structures are adjusted to counteract the perceived blood pressure increase. Electrical stimulators directly activating afferent baroreflex nerves were developed years earlier but failed for technical reasons. Recently, a novel implantable device was developed that produces an electrical field stimulation of the carotid sinus wall. Carefully conducted experiments in dogs provided important insight in mechanisms mediating the depressor response to electrical carotid sinus stimulation. Moreover, these studies showed that the treatment success may depend on the underlying pathophysiology of the hypertension. Clinical studies suggest that electrical carotid sinus stimulation attenuates sympathetic activation of vasculature, heart, and kidney while augmenting cardiac vagal regulation, thus lowering blood pressure. Yet, not all patients respond to treatment. Additional clinical trials are required. Patients equipped with an electrical carotid sinus stimulator provide a unique opportunity gaining insight in human baroreflex physiology.

Non-pharmacological methods in the treatment of resistant hypertension.

INTRODUCTION: Arterial hypertension is the most common chronic cardiovascular disease affecting about 25% of the adult population. Meta-analyses have demonstrated a linear relationship between blood pressure and the risk of cardiovascular events. Resistant hypertension defined as failure to reach blood pressure targets despite treatment with three antihypertensive drugs including a diuretic represents a serious clinical problem. It has been estimated that it affects between 8.9% and 12.8% of all treated hypertensive subjects. In resistant hypertension the optimal blood pressure is illusive despite very well tailored therapy. OBJECTIVE: Management of resistant hypertension is exactly the field where blood pressure-controlling non-pharmacological methods fit best. The present article aims at throwing light on these methods' principles of action, on who the target patient groups are and the respective results. Two methods are especially reviewed here: the carotid baroreflex stimulation and the transcatheter renal sympathetic denervation. Current results from the use of renal denervation suggest stable efficiency of the method, the results becoming significant 6 months after the procedure is applied and sustained for two years in the follow-up. As much as 90% of the treated patients respond to the procedure. The transcatheter renal denervation is associated with only 2.61% of procedural complications. The baroreflex carotid stimulation, too, is known to produce a stable effect on blood pressure: the effect become obvious at 12 months in 88% of the treated subjects. The neurologic complications associated with the procedure are reported to occur in 4.4% of cases. CONCLUSION: The present review article clearly demonstrates that non-pharmacological methods for treatment of resistant hypertension show great promise despite some open questions concerning their long term effects and procedural safety.

Lowering of blood pressure by chronic suppression of central sympathetic outflow: insight from prolonged baroreflex activation.

Device-based therapy for resistant hypertension by electrical activation of the carotid baroreflex is currently undergoing active clinical investigation, and initial findings from clinical trials have been published. The purpose of this mini-review is to summarize the experimental studies that have provided a conceptual understanding of the mechanisms that account for the long-term lowering of arterial pressure with baroreflex activation. The well established mechanisms mediating the role of the baroreflex in short-term regulation of arterial pressure by rapid changes in peripheral resistance and cardiac function are often extended to long-term pressure control, and the more sluggish actions of the baroreflex on renal excretory function are often not taken into consideration. However, because clinical, experimental, and theoretical evidence indicates that the kidneys play a dominant role in long-term control of arterial pressure, this review focuses on the mechanisms that link baroreflex-mediated reductions in central sympathetic outflow with increases in renal excretory function that lead to sustained reductions in arterial pressure.

Timing and efficacy of alternative methods of sympathetic blockade.

Despite the presence of seven different antihypertensive drug classes and over 120 different antihypertensive medications, about 48 % of the 75 million people with hypertension are not reaching their target blood pressure goals. One of the reasons for this lack of control is the failure to adequately inhibit the sympathetic nervous system. Consequently, alternative therapies have been attracting interest. Recent technical advances targeting the sympathetic over-activity of the carotid sinuses (baroreflex activation therapy, BAT) and the renal sympathetic nerves (renal denervation therapy, RDT) have renewed interest in invasive therapies for the treatment of drug-resistant hypertension. Encouraging results from the recent Rheos Pivotal and Symplicity HTN-2 trials on the safety and efficacy of BAT and RDT, respectively, indicate that invasive approaches can safely reduce blood pressure in patients with resistant/refractory hypertension. These approaches, while still experimental in the US, are appropriate for those on more than three fully tolerated doses of antihypertensive medications whose blood pressure is not at goal, i.e. <140/90 mmHg. The present review is focused on the clinical implications of these two technics and when they are appropriate.

Effect of carotid sinus nerve blockade on hemodynamic stability during carotid endarterectomy under local anesthesia.

OBJECTIVE: To find out whether routine carotid sinus nerve blockade with lidocaine during carotid endarterectomy under local anesthesia results in perioperative changes in blood pressure and heart rate. METHODS: This was a prospective, randomized, single-center study, conducted in a university hospital. A total of 120 patients undergoing carotid endarterectomy under local anesthesia were randomly assigned to three equal groups. Patients with previous carotid endarterectomy were excluded from the study. During the operation the carotid sinus area was infiltrated as follows: group 1 received 2 mL of 1% lidocaine; group 2 received 2 mL of 0.9% NaCl; and group 3 received no infiltration. The carotid sinus nerve was spared in all patients. Blood pressure and heart rate were invasively monitored during the operation and 12 hours postoperatively over the radial artery cannula. Preoperative values were calculated as a mean of three noninvasive measurements on the day before surgery. Data comprised of arterial blood pressures and heart rates from 32 time point measurements for each patient were analyzed. RESULTS: There was no significant difference among the groups regarding the mean arterial blood pressures and mean heart rates during the follow-up period. There was no significant difference among groups regarding the number of patients that required vasoactive therapy at any time of measurement. CONCLUSION: Routine infiltration of carotid sinus area with 1% lidocaine during carotid endarterectomy performed under local anesthesia has no significant impact on mean arterial blood pressure and heart rate during the operative procedure and the following 12 postoperative hours.

Rheos: an implantable carotid sinus stimulation device for the nonpharmacologic treatment of resistant hypertension.

Hypertension is a highly prevalent disorder in the United States. Of particular concern is resistant hypertension, which by definition is hypertension that cannot be adequately treated by conventional 3-drug regimens. The Rheos Baroreflex Hypertension Therapy System is a new implantable device that can treat patients with hypertension resistant to multidrug therapy, by activating the carotid baroreflex through electrical stimulation of the carotid sinus wall. Recent studies in both normotensive and hypertensive canine models have demonstrated sustained and clinically relevant reductions in arterial pressure and sympathetic activity with prolonged baroreflex activation. Clinical trials designed to evaluate the efficacy and safety of this therapy in patients with treatment resistant hypertension, are now ongoing in both Europe and the United States.