Hypertension is a common and serious problem that is the major cause of morbidity and mortality worldwide.1–3 Over 70 million people in the US are affected by high blood pressure (BP) that requires treatment, and nearly one-third of the adult population in the US have a BP of ≥140/90mmHg, which is the defined cut-off value for hypertension.2,4 It is estimated that over 44% of people in Europe are affected by high blood pressure.5 Studies have shown that there are several risk factors for hypertension, including body mass index (BMI),6,7 cholesterol,8 age,7 family history,7 gender,9 race/ethnicity10 and a sedentary lifestyle.6,11 Although there are many effective pharmacotherapies available, nearly 35% of patients with hypertension have a form that cannot be controlled by medication.12,13 Reasons for this include poor compliance and inadequate dosing.3 If these reasons are discounted, it is estimated that 13 to 15% of patients have drug-resistant hypertension (RH).12,14,15 The current definition of RH is failure to achieve a blood pressure of less than 140/90mmHg despite taking three antihypertensive medications (including one diuretic).3 Many people with RH remain resistant despite aggressive medical therapy with five or six antihypertensive medications: this necessitates the search for alternative antihypertensive management strategies.
Carotid sinus baroreceptors play a central role in BP regulation via different inputs to the cardiovascular regulatory centres of the medulla in response to changes in blood pressure, modulating the output of the sympathetic activity.16,17 Chronic activation of the sympathetic nervous system is a major component in the development of essential hypertension.18 Early studies have demonstrated that electrical activation of the carotid sinus of normotensive canines, renally-induced hypertensive canines and humans leads to a decrease in BP.19,20 Furthermore, carotid baroreceptors have a recognised role in short-term blood pressure regulation,17 but were thought to have a less important role for long-term regulation.21 However, recent studies have demonstrated that prolonged carotid baroreceptor activation therapy can lower BP.22,23 Thus, there is renewed interest in developing an electrical carotid sinus activator to treat RH. This article will evaluate carotid baroreceptor activation as treatment for RH and related conditions.
The Baroreflex in Hypertension – Pre-clinical Studies
The baroreflex is a negative feedback mechanism for blood pressure regulation and its physiology is well established.24,25 An increase in BP activates the baroreceptors present in the carotid sinus and aortic arch,26 which ultimately leads to decreased sympathetic activity in the heart, peripheral vasculature and kidneys and increased parasympathetic activity in the heart. These effects lead to a decrease in blood pressure.16 Conversely, a fall in BP has an opposite effect on the autonomic nervous system.17
While the baroreflex is important in regulating short-term blood pressure changes,17 baroreceptors can re-set to a higher activation threshold in response to chronic elevations in BP27–29 and also become less sensitive.30,31 This re-setting attenuates the inhibition of sympathetic activity and, since chronic activation of the sympathetic nervous system plays an important role in essential hypertension, this re-setting prevents intrinsic control of long-term hypertension.
The effect of carotid sinus activation on BP regulation has been investigated in canines by Lohmeier and colleagues. Activation was carried out by implanting electrodes around both carotid sinuses and using an externally adjustable pulse generator to electrically activate the carotid baroreflex.32 Chronic activation of the baroreceptors resulted in an initial substantial reduction in mean arterial pressure (MAP) and this was maintained for seven days of baroreflex activation.32 Reductions in plasma noradrenaline concentration and heart rate (HR) were also observed. Following termination of the stimulation, the haemodynamic responses and noradrenaline levels returned to baseline levels. Similar results have been observed in obesity-induced canines.33 Sustained BP lowering usually results in activation of the renin–angiotensin system, with a subsequent angiotensin-II-induced retention in water and salt;17 however, no changes in renin levels were observed in the canine studies conducted by Lohmeier and colleagues. This suggests that an important mechanism through which carotid baroreflex stimulation results in long-term BP regulation is renal sympatho-inhibition with a resultant increase in natriuresis. This mechanism has also been implicated by other studies in canines.33
The effect of renal denervation on the efficacy of carotid baroreflex stimulation has also been tested in canines.22 The carotid baroreflex was activated for seven days before and after bilateral renal denervation. Similar values for MAP, plasma noradrenaline concentration, plasma renin activity and sodium excretion were observed before and after denervation. This illustrates that renal sympatho-inhibition is not the only mechanism for achieving long-term reductions in arterial pressure during chronic baroreflex activation. Possible reasons for this could include elevated atrial natriuretic peptide (ANP) levels.22 The studies by Lohmeier and colleagues demonstrate that chronic rises in BP can be effectively regulated by prolonged electrical activation of the carotid baroreflex in canine models.
A Novel Implantable Baroreflex Activation System
Very early experiences with direct baroreceptor activation were hampered by technical limitations.34,35 More recently a novel implantable carotid sinus baroreceptor system (Rheos System®, CVRx Inc, US) has been evaluated. Initial studies with an earlier version of the device in 11 patients showed that electrical activation of the barorereceptors produced a graded voltage-dependent drop in blood pressure.36
The Rheos System contains bilateral carotid sinus leads (CSL) and a battery-powered impulse generator (IPG).37 The IPG is externally programmable via directional telemetry, allowing the adjustment of stimulation parameters. The CSL conducts the activation energy from the IPG to the carotid sinuses, resulting in activation of the baroreceptor fibres present in the carotid sinus wall and, consequently, activation of the baroreflex.37,38 Tordoir et al. and Illig et al. previously described in detail the surgical implant procedure for the device.37,38 In brief, on the day of the surgery the patient’s morning doses of antihypertensive medications are withheld, and aspirin and beta-adrenergic blockers are administered unless contraindicated. The level of carotid bifurcation is marked on each side using ultrasound guidance. A catheter is placed in the non-dominant radial artery for continuous monitoring of the patient’s BP. The surgical procedure is carried out under general anaesthesia and involves three stages: anaesthetic induction and exposure of the carotid bifurcation, carotid sinus mapping and electrode positioning at the location with the highest density of baroreceptors and lead tunneling procedure (subcutaneously) to the IPG and IPG implantation under the skin near the collarbone.
The patient is seen two days after implantation to check that the device provides optimal BP lowering. The device is then deactivated to allow wound healing, and reactivated a month after implantation. Tests are then carried out to determine the most optimal setting of the device for the specific patient.
Baroreflex Activation in Hypertensive Patients
An early proof-of-concept study was carried out in humans to test whether a Rheos-type device to activate the carotid baroreflex was a treatment option for patients with RH.36 Patients undergoing elective surgery (n=11) for carotid artery surgery were enrolled in this study. Electrodes were temporarily placed on the wall of the carotid sinus wall and after obtaining a steady state baseline of BP and HR, an electric current was applied to activate the baroreceptors. This current was increased in one-volt increments. The results showed that when the current was acutely applied, a voltage-dependent and significant reduction in BP was observed.
The European phase II Device Based Therapy of Hypertension (DEBuT-HT) study is an open-label, single group designed to evaluate the safety and efficacy of the Rheos System in patients with severe and RH despite treatment with at least three concomitant antihypertensive drugs. The first published data from the study, in 17 patients with mean baseline blood pressure of 177/99 and heart-rate of 80 beats/minute showed that system testing performed one to three days post-operatively resulted in significant mean reductions in systolic BP, diastolic BP and heart-rate of 28mmHg, 16mmHg and 8 beats/minute, respectively. At three months post-implant, baroreflex activation produced a durable response.37 Preliminary data, presented in abstract form have also been promising. One year of chronic therapy with the Rheos System in 15 patients resulted in a significant decrease in resting systolic and diastolic BP and HR compared with pre-implant.39 After one year of therapy there was a trend towards decreased BP variability and increased HR variability, indicating inhibition of sympathetic tone and an increased vagal tone, respectively. The effect on BP was sustained after two years of chronic therapy in 16 patients with a significant mean reduction for systolic BP, diastolic BP and heart-rate of 35mmHg, 24mmHg and 12 beats/minute, respectively.40 No unanticipated adverse events were reported in the DEBuT-HT study. At one-year, chronic baroreceptor activation did not impair overall renal function.41 Long-term follow-up of the DEBuT-HT study participants is under way and will monitor the course of the disease and baroreflex stimulation treatment safety and efficacy. Full publication of the data from initial phase of DEBuT-HT is anticipated.
Preliminary data from a US phase II study, the Rheos Feasibility Trial, have also been presented in abstract form. Early data from 10 patients with RH despite a median of six antihypertensive medications showed that device implantation was not associated with significant morbidity and no adverse events were attributable to the device. Three months of active Rheos therapy produced significant mean reductions in systolic BP and diastolic BP of 22mmHg and 18mmHg, respectively.42
Combined data from the European and US cohorts have also been published in abstract form. Rothstein et al. assessed the orthostatic blood pressure and HR response in 29 patients prior to Rheos activation and after three months of active therapy.43 There was no significant additional hypotension after three months of Rheos therapy compared with the transient drop in systolic pressure and HR under pre-implant conditions. During the orthostatic stress, diastolic BP demonstrated the anticipated slight increase with standing pre-implant and stabilised following three months of therapy. This suggests that Rheos therapy does not cause excessive hypotension during upright posture.
An analysis of combined data from 27 patients from European and US cohorts showed that after six months of active Rheos therapy systolic BP was significantly reduced by an average of 21mmHg and diastolic BP was significantly reduced by an average of 16mmHg. A significant reduction in HR of 9 beats/minute was also observed at six months.44 Combined preliminary data from DEBuT-HT and the Rheos Feasibility Trial on ambulatory BP from 16 patients demonstrated that one year of Rheos therapy produces clinically significant reductions in ambulatory systolic BP.45 The above studies provide encouraging data on the prospect of utilising chronic baroreflex activation in treating RH in clinical practice. A phase III pivotal trial is currently under way, with a planned enrollment of 300 patients.
The Design of the Phase III Rheos Pivotal Trial
This phase III prospective, randomised, double-blind, parallel-design, multicentre clinical trial is ongoing and currently recruiting participants. Its purpose is to demonstrate the efficacy and safety of the Rheos System in subjects with RH. Patients will be randomised at a 2:1 ratio into ‘on’ or ‘off’ groups. The patients will be kept in these groups for the next six months and after this period all patients will receive active therapy. All patients will be maintained on current antihypertensive medications until at least one year post-implantation. The primary efficacy objectives of the phase III study include demonstrating a clinically significant reduction (defined as 10mmHg) of office cuff systolic BP at six months post-device, and a sustained response to therapy 12 months after device activation.
Baroreflex Activation as a Therapy for Heart Failure?
The role of autonomic activation in the setting of chronic heart failure (HF) is well established and is the target of modern pharmacotherapy of HF.46–49 As the Rheos System acts through modulating the autonomic nervous system, long-term carotid baroreflex activation therapy has been investigated in canine models of heart failure. Gupta et al. have shown that three months of carotid baroreflex activation therapy in canines with HF results in normalised messenger RNA (mRNA) expression of all nitric oxide synthase (NOS) subtypes.50 Fluctuations in the levels of the NOS are associated with the release of pro-inflammatory cytokines and cardiomyocytes apoptosis in HF, thus this study suggests that chronic baroreflex activation therapy can result in an improvement in left ventricular function of HF canines.50 Cardiac β-adrenergic receptor (β-AR) signalling is also impaired in HF, leading to desensitisation of the myocardium to catecholamines. A study examining the effects of three months baroreflex activation therapy on mRNA expression of β-AR and guanine nucleotides in the left ventricular myocardium of HF canines has shown that baroreflex activation therapy normalises mRNA expression of key components of the β-AR signal transduction pathway.51 In addition, Zucker et al. showed that in canines with pacing-induced HF, survival was significantly increased in canines undergoing chronic carotid baroreceptor activation compared with controls (60.7±7.5 days versus 27.4±3.3 days, respectively; p<0.01).52
During the DEBuT-HT study; the echocardiograms for 18 patients with early-stage heart failure were obtained at baseline (pre-implant) and at three and 12 months post-implantation (see Table 1).53 These patients had left ventricular hypertrophy (LVH). Chronic Rheos therapy in these early-HF patients remodels cardiac structure and improves function and therefore seems to be beneficial for early HF treatment. Larger studies with long-term follow-up are needed to assess the cardioprotective effects of Rheos therapy-induced LVH reduction.54
Other Uses of Baroreflex Activation
Studies are needed to investigate the other proposed indications for Rheos therapy, such as severe vascular injury and target organ damage. Another proposed indication is to use Rheos therapy in the early stages of target organ damage, such as left ventricular hypertrophy with a normal systolic and diastolic function, so that the disease can be controlled before it increases in severity.
The mechanism of action for treating these diseases could include altering the vasculature. It has been previously discussed that the Rheos therapy lowers BP through more than one mechanism. If the heart is considered a being part of the vasculature, then one mechanism of BP lowering could be through remodelling of the vasculature. Studies investigating the use of Rheos therapy in HF should help to identify the effect of vasculature remodelling on BP regulation.
Conclusion
Hypertension, a common and serious condition, is the major cause of morbidity and mortality worldwide. Treatment is generally through administration of antihypertensive medications; however, up to 15% of patients are resistant to these medications. Resistant hypertension often does not respond to aggressive medical therapy, which creates a significant need for alternative therapies. Carotid sinus baroreceptor activation offers an attractive alternative, and early clinical trials with a novel implantable device have been encouraging. A phase III trial that is currently under way will add to the knowledge of both the understanding of Rheos therapy and the safety and efficacy of this therapeutic option in RH. Interestingly, the observation that baroreflex activation therapy has been associated with improved cardiac structure and function in canines and humans with heart failure suggests that it may have clinical applications beyond the treatment of RH. Indeed, feasibility studies are currently under way to test the potential of Rheos therapy in heart failure.