Hypertension is a major cause of morbidity and mortality worldwide.1–3 In the US, around 25% of the adult population has a blood pressure (BP) of ≥140/90mmHg, which is the defined cut-off value for hypertension.3 Although there are many effective pharmacotherapies available, many patients are not adequately controlled on their current antihypertensive regimens. The National Health and Nutrition Examination Survey (NHANES; 2003–2004) showed that only 58% of patients receiving treatment for hypertension achieved a BP of <140/90mmHg.4 When factors such as an inadequate dosing regimen, poor patient adherence, and secondary hypertension2,5,6 are discounted, nearly 5–10 million patients in the US are estimated to have drug-resistant or -refractory hypertension. The American Heart Association (AHA) Professional Education Committee of the Council for High BP Research currently defines resistant hypertension as BP that remains above the goal level despite the concurrent use of three antihypertensive agents of different classes.5 However, it should be noted that the definition includes patients whose BP is controlled with the use of more than three medications; that is, patients whose BP is controlled but require four or more medications should be considered resistant to treatment. Importantly, although the number of medications required under the current definition is arbitrary, it provides a means of identifying patients who may benefit from more extensive diagnostic and special therapeutic considerations. A central role in BP regulation is attributed to the arterial baroreflex.7,8 The carotid sinus baroreceptors respond to changes in BP with increased afferent input to the cardiovascular regulatory centers of the medulla, leading to a decrease in sympathetic activity.7,8 Thus, this system provides a potent buffering mechanism that offsets short-term fluctuations in BP. An important component in the development of hypertension is chronic activation of the sympathetic nervous system (SNS).9 Resistance to antihypertensive drug effects has been partly attributed to the failure of currently available therapies to adequately block periodic and ongoing increases in sympathetic activity. Preliminary data have shown decreases in BP with electrical stimulation of the carotid sinus of normotensive canines, obesity- and renally induced hypertensive canines, and humans.10,11 While carotid baroreceptors have a well-established role in the short-term regulation of BP,8 they have been thought to play a less important role in its long-term regulation.12
However, it has been demonstrated that chronic baroreceptor stimulation therapy can decrease BP.12,13 Such data have led to interest in the development of an electrical carotid sinus stimulator providing ‘baroreceptor stimulation therapy’ that may both complement pharmacotherapy and facilitate BP control. The role of carotid baroreceptor stimulation as a therapeutic option for drug-resistant hypertension and related conditions will be further addressed in this article.
The Arterial Baroreflex in Hypertension
The arterial baroreflex regulates BP by acting through a negative feedback mechanism. The physiology of this reflex is well established,14,15 where an increase in BP leads to stimulation of the carotid and aortic arch baroreceptors,16 eventually leading to decreased sympathetic activity at the level of both the kidneys and the peripheral vasculature. Baroreceptor stimulation can also reduce sympathetic and increase parasympathetic activity in the heart. These effects collectively lead to a decrease in BP.7 The role of the arterial baroreflex in short-term BP regulation is well-recognized.8 However, in response to chronic elevations in BP, baroreceptors can reset to a higher activation threshold17–19 and diminished sensitivity.20,21 The chronic activation of the SNS and its effects on a systemic or on a regional organ-specific basis is important in the development of essential hypertension. The resetting of the baroreceptor attenuates the anticipated pressure-related inhibition of sympathetic activity, preventing natural reflex control of elevated BP.
Baroreflex Activation—Pre-clinical Studies
Lohmeier and colleagues have investigated the effect of carotid sinus stimulation on BP regulation in canines. In their studies, electrodes were chronically implanted around both carotid sinuses, with the electrodes connected to an externally adjustable pulse generator.22 Stimulation was carried out by using the pulse generator to electrically activate the carotid baroreflex.22 In these studies there was an early and considerable reduction in mean arterial pressure (MAP) when the baroreceptors were chronically stimulated.22 This reduction was maintained throughout the seven days of baroreflex activation,22 indicating a short-term durable response. There was also a decrease in plasma noradrenaline concentration and heart rate (HR).
The hemodynamic responses and plasma noradrenaline concentration returned to baseline levels once the stimulation was terminated. Lohmeier et al. have shown similar results in canines with an obesity-related model of hypertension.23 While sustained BP lowering tends to activate the renin–angiotensin system with a subsequent angiotensin II-induced retention of salt and water,8 no changes in renin levels were observed by Lohmeier and colleagues with carotid sinus stimulation in studies of experimentally induced hypertension in various canine models.17,23 These data suggest that a critical mechanism through which carotid baroreflex stimulation results in long-term BP regulation is renal sympatho-inhibition and, consequently, natriuresis, despite there being lower BP. Lohmeier et al. have also tested the effect of renal denervation on the efficacy of carotid baroreflex stimulation in canines.13 They activated the carotid baroreflex for seven days before and after bilateral renal denervation and observed similar values for mean arterial pressure, plasma noradrenaline concentration, plasma renin activity, and sodium excretion before and after denervation. This indicates the presence of mechanisms other than renal sympatho-inhibition that can also help achieve long-term reductions in arterial pressure during chronic baroreflex activation. The studies by Lohmeier and colleagues demonstrate that in canine models chronic elevations of BP can be effectively regulated by prolonged electrical stimulation of the carotid baroreflex.
A Novel Implantable Baroreflex Activation System
Despite initial promising findings, technical limitations hampered the early experiences with direct carotid sinus nerve stimulation in the 1970s.24,25 Undesirable technical features included damage to the carotid sinus nerves during the surgical procedure and the potential for current spread around the implanted electrode. Moreover, the advent of newer and more effective antihypertensive drugs contributed to a decline in interest in a medical device approach. However, more recently interest has been revived in the concept of non-pharmacological control of BP by prolonged baroreflex activation, with the clinical evaluation of a novel implantable carotid sinus baroreceptor system (the Rheos® System, CVRx Inc, US).
Mechanism of Action
The Rheos System is an externally programmable battery-powered implantable pulse generator (IPG) connected to bilateral carotid sinus leads (CSLs).26 Directional telemetry makes it possible to externally program the IPG, allowing adjustment of stimulation parameters.26 These parameters include the amplitude of voltage and the frequency and duration of impulses.26 Activation energy is conducted from the IPG to the carotid sinuses by the CSLs, leading to stimulation of the baroreceptor fibers in the carotid sinus wall and, consequently, stimulation of the baroreflex.26,27 The central nervous system perceives this increase in baroreceptor fiber activity in a manner such that sympathetic outflow decreases.
Surgical Implantation Procedure
The surgical implantation procedure for the Rheos System has been previously described in detail.26,27 Briefly, on the day of the surgery the patient’s morning doses of antihypertensive medications are withheld. Aspirin and beta-adrenergic blockers are administered unless contraindicated. The surgical procedure is carried out under general anesthesia. The first stage involves anesthetic induction and exposure of the carotid bifurcation. This is followed by carotid sinus mapping on each side of the neck by identifying the location on the carotid sinus that when stimulated elicits the greatest drop in BP. Once identified, the electrodes (attached to the leads) are implanted at the best locations on each side. The CSLs are then subcutaneously tunnelled to the IPG and the IPG implanted under the skin in a pocket on the right side of the chest beneath the collarbone. The time required for exposure of the carotid artery and implantation of the pulse generator is similar to that involved in carotid endarterectomy procedures and pacemaker implants, respectively. Placement of the electrodes in their optimal location and connection of the leads to the IPG may extend the procedure time by approximately one hour. This is determined largely by the carotid mapping stage and depends on the anatomy of the carotid artery. As indicated, antihypertensive medications are administered in the post-operative period. One or two days post-surgery, the device is activated to identify the settings that provide optimal BP lowering and the programming parameters are put in. The device is turned off for a month to allow time for wound healing and is reactivated after one month, when tests are carried out to determine the best settings for the patient. The exact timing of device activation has, to date, related to protocol-specific criteria.
Baroreflex Activation in Hypertensive Patients
An early version of the Rheos device was evaluated in a proof-of-concept study. The aim was to test whether carotid baroreflex stimulation using this device was a treatment option for patients with resistant hypertension.28 The study recruited 11 patients undergoing elective carotid surgery. Electrodes were placed on the carotid sinus wall. Once steady-state baseline levels of BP and HR were obtained, an electric current was applied to stimulate the baroreceptors (increased in one-volt increments). A graded voltage-dependent and highly significant reduction in BP was observed upon acute electrical stimulation of the baroreceptors.28
The Device-based Therapy of Hypertension Study
The Device-based Therapy of Hypertension (DEBuT-HT) study was designed to evaluate the safety and efficacy of the Rheos System in severely hypertensive patients despite treatment with multiple antihypertensive drugs. It was a phase II European-based, open-label, single-group study. The first published data from the study showed that system testing performed one to three days post-operatively in 17 patients with mean baseline BP of 189.6±27.5/110.7±15.3mmHg resulted in significant mean maximum reduction for systolic BP, diastolic BP and heart rate of 28±22mmHg, 16±11mmHg, and 8±4 beats/minute, respectively. Furthermore, the response to baroreflex stimulation remained intact at three months post-implant.26 Preliminary data from the study have been presented in abstract form. At the time of reporting, 10 of the 15 patients implanted with the Rheos System had completed one year of chronic therapy. There was a significant decrease in resting systolic and diastolic BP and HR compared with pre-implant levels.29 A trend toward decreased BP variability and increased HR variability was also observed. These trends indicate inhibition of sympathetic tone and an increase in parasympathetic tone, respectively.29 The effect on BP was sustained after two years of chronic therapy with the device in 16 patients.30 No unexpected serious adverse events were reported in the DEBuT-HT study. A long-term follow-up of the study, the Device-based Therapy in Hypertension Extension Trial (DEBuT-HET), is ongoing and will further monitor the safety and efficacy of baroreflex activation, as well as its impact on hypertension-related end-organ disease parameters. Full publication of the data from the initial phase of DEBuT-HT is expectantly awaited.
The Rheos Feasibility Trial
Preliminary data from the Rheos Feasibility Trial have also been presented in abstract form.31 This was a US-based phase II trial in which 10 patients with resistant hypertension despite a median of six antihypertensive medications were surgically implanted with the Rheos System. Device implantation was not associated with significant morbidity. The results of the trial showed that there were significant mean reductions in systolic and diastolic BP of 22 and 18mmHg, respectively, after three months of active Rheos therapy.
Combined Data from the European and US Cohorts
The combined data from the two cohorts have been published in abstract form and updated results were recently presented at the American College of Cardiology 58th Scientific Sessions at the Late-Breaking Clinical Trials III: Emerging Technologies Session. Dr Rothstein et al. analyzed combined data from 22 patients from European and US cohorts. The analysis showed that after three years of active Rheos therapy, systolic and diastolic BP were significantly reduced by averages of 31 and 22mmHg, respectively. There was also a significant reduction in heart rate.32
Effect of Activation on Renal Hemodynamics
The effect of chronic baroreceptor activation on renal hemodynamics was also investigated in the DEBuT-HT study.30 The results showed that in 12 patients who had completed one year of Rheos therapy, BP was significantly decreased, while effective renal plasma flow (ERPF) showed a trend to decrease and glomerular filtration rate (GFR) was unchanged. There was an increase in BP, a trend to increase in effective renal plasma flow (ERPF), and unchanged GFR when therapy was turned off for one hour. Thus, chronic activation of the baroreflex and the resultant fall in BP seems not to impair overall renal function.
Effect of Activation on the Development of Orthostatic Hypotension
As previously mentioned, the combined data from the European and US cohorts have been published in abstract form. Rothstein et al. evaluated whether baroreflex activation results in orthostatic hypotension.33 The orthostatic BP and HR response in 29 patients was assessed before activation of the Rheos System and after three months of active therapy.
There was no significant orthostatic hypotension after three months of active therapy compared with the momentary drop in systolic BP under pre-implant conditions. During orthostatic stress pre-implant, there was a slight increase in diastolic BP when standing. However, diastolic BP stabilized following three months of active therapy. These results suggest that baroreflex activation is not associated with excessive hypotension during upright posture. The above studies provide promising initial data on the possibility of utilizing chronic activation of the baroreflex for the treatment of resistant hypertension in clinical practice. A phase III pivotal trial is currently under way in over 50 centers worldwide, with a planned enrollment of 300 patients.
The Design of the Phase III Rheos Pivotal Trial
The Rheos Pivotal trial has been designed to be a prospective, randomized, double-blind, parallel design, multicenter trial. The aim is to evaluate the efficacy and safety of the Rheos System in patients with drug-resistant hypertension. Once the patients are implanted with the Rheos device, they will be randomized in a 2:1 ratio into two groups: Rheos therapy on or off (placebo) groups with continuation of background antihypertensive therapy. The patients will be kept in their respective group for the next six months and, after this period, all patients will receive active therapy. Subjects and treating physicians will not be informed as to treatment allocation. In my opinion, the length of time that individuals might be assigned to placebo (six months) is excessive. A placebo response would almost certainly manifest within three months of implantation; however, the US Food and Drug Administration (FDA) felt strongly that at least six months of off therapy was necessary. Pre-implant antihypertensive medications will be continued in all patients until at least one year post-implantation unless changes in BP warrant medication discontinuation or dosage reduction. Currently, there is not a clear protocol for sequential removal of medication in the well-controlled patient with baroreceptor activation in the on mode, although this is of interest and under evaluation, as 26% of patients in the European and US feasibility studies achieved a BP <140/90 at two years of follow-up.32 The primary objectives of this trial include demonstrating a sustained response to therapy through 12 months post-device activation, and a clinically significant reduction (10mmHg) of office cuff systolic BP at six months post-device activation compared with placebo (device in the OFF position).
Baroreflex Activation as a Treatment for Heart Failure?
Sympathetic activity, both systemic and regional, has a crucial role in the setting of chronic heart failure (CHF).34–37 Therefore, it is often targeted with contemporary pharmacotherapy of CHF.34–37 Chronic baroreflex activation therapy has been investigated in canine models of heart failure as the Rheos System acts through modulation of the autonomic system.
Zucker et al. chronically stimulated the baroreflex in canines with pacing-induced HF. There was an improvement in survival of these canines when they were subjected to chronic carotid baroreceptor activation compared with control dogs (68.1±7.4 versus 37.3±3.2 days; p<0.01).38 Plasma norepinephrine levels measured after 31 days of activation therapy were lower compared with the control group. (401.9±151/5 versus 1,121.9±389.1pg/ml).38 It is known that fluctuations in nitric oxide synthase levels are linked to cardiomyocyte apoptosis and the release of pro-inflammatory cytokines in HF.39 A recent study showed that messenger RNA (mRNA) expression of all nitric oxide subtypes (NOS) was normalized after three months of baroreflex activation therapy in canine models of HF.39 Chronic baroreflex activation therapy may improve left ventricular function in canines with HF.39 A study examined the effect of three months of baroreceptor activation therapy on mRNA expression of β-adrenergic receptor (β-AR) and guanine nucleotides in the left ventricular myocardium of HF canines.40 Cardiac β-AR signaling is impaired in HF, leading to desensitization of the myocardium to catecholamines. Gupta et al. showed that baroreflex activation therapy normalized mRNA expression of key components of the β-AR signal transduction pathway.4 The above studies suggest that chronic activation of the baroreflex may be a therapeutic option for heart failure.
Echocardiograms for 18 patients with early-stage HF and left ventricular hypertrophy were obtained at baseline (acquired before implant) and at three and 12 months post-implantation.41 The results (see Table 1) show that chronic baroreflex activation in early-HF patients remodels cardiac structure and improves function. Therefore, the Rheos System appears to offer some benefits to the patient with early-stage HF. The cardioprotective effects of Rheos-therapy-related changes in left ventricular hypertrophy need to be evaluated in larger studies with long-term follow-up.42
Role of Baroreflex Activation in Future Clinical Practice
The Rheos System is aimed at improving the status of poorly controlled patients by allowing them to ‘respond’ more efficiently to their antihypertensive medications. In some patients, it may reduce or completely eliminate the need for antihypertensive medications. It is specifically targeted at hypertensive patients who are drug-resistant. It is still in the investigational stage and not yet approved, and in the future patients receiving this therapy will have to be carefully selected. Future clinical practice will also require a more accurate definition of resistant hypertension and the involvement of experienced and seasoned healthcare professionals to correctly diagnose the patient. Importantly, the programmability of the Rheos system enables the treating physician to personalize treatment to the needs of the patient. Consequently, patients would need to be monitored post-implantation by people with exceptional management skills and understanding of the programming protocols. Clinical trials to further elucidate the role of Rheos in the treatment of heart failure may lead to its use in other disease settings. The Rheos System received investigational device exemption (IDE) status in the US and its safety and effectiveness are currently being evaluated in the Rheos Pivotal Trial. It has received CE Mark approval in Europe and was approved for marketing based on the clinical studies conducted in Europe and the US. Worldwide, 225 patients have been implanted, with 3,465 months or 288 years of experience, with the longest follow-up being five years.
The exact prevalence of resistant hypertension is unknown; although a forced titration study of a large diverse hypertensive cohort would be required to accurately determine its prevalence, it is no doubt high. Moreover, treatment resistant hypertension does not respond to aggressive medical therapy, creating a significant need for alternative therapeutic options. For this patient population, a promising alternative is the prolonged activation of the carotid sinus baroreceptors. A phase III pivotal trial is ongoing, and will further evaluate the safety and efficacy of prolonged baroreflex activation as complementary therapy to antihypertensive medications in patients with resistant hypertension. This treatment option may also have clinical applications beyond treatment of resistant hypertension, as this strategy has been associated with improved cardiac structure and function in both experimental and human forms of heart failure. Although device therapy in HF is still early and very much experimental, the results from the ongoing feasibility trials are anticipated, and will further elucidate the potential of Rheos therapy in HF.