Baroreceptors are located in the aortic arch and at the carotid sinus level . In humans, the carotid and the aortic baroreceptor systems cannot be studied separately unless one of these would be eliminated. Hence, all we know about the functioning of the baroreceptor system in man is based upon the two acting in concert. Nevertheless, it is possible to modulate the input signal at the level of the carotid system only, for instance by applying a positive or negative pressure on the neck by means of a neck chamber. This experimental technique has been very useful to enhance our understanding of the baroreceptor system [5]. Contrary to what is often believed, baroreceptors do not respond to pressure changes but to changes in distension of the vascular wall. In other words, the input signal (a change in transmural pressure) essentially comes from within the vascular lumen. This is also what happens when one applies the neck chamber technique. Baroreceptor activation therapy (BAT), on the other hand, stimulates sensitive elements at the outside of the vascular wall. Indeed, stimulation electrodes are placed at or around the carotid artery at a spot where acute stimulation produces the greatest response. Whether in physiological terms, the effect of external stimulation is comparable to that of stimulation from within the vessel is presently unknown .

Current devices for BAT stimulate the carotid baroreceptor area only. When one applies BAT, it is necessary to consider several stimulation characteristics during the programming such as start and stop times, ramp function, dose settings, burst settings, pulse amplitude, pulse width, and pulse frequency. In case of bilateral stimulation, this has to be decided on separately for the left and right lead. The most common approach is to set the voltage and the frequency depending on the prevailing level of blood pressure and heart rate and the patient’s response to stimulation. Sometimes it is necessary to use different settings during daytime and nighttime. At any rate, it is a matter of trial and error to find the optimal settings in a particular patient .

Another important question is whether one should stimulate the baroreceptor area at both sides or unilaterally. Early data in animals suggested that unilateral stimulation with a bipolar electrode which was attached directly to the carotid sinus nerve was sufficient to reduce blood pressure [6]. In man, studies with BAT initially involved bilateral stimulation but the most recent device has been developed for unilateral stimulation only. Preliminary data indicate that stimulation at one side is indeed as effective as bilateral stimulation [7] .

The idea behind BAT in hypertension is not novel as the technique was already applied some 50 years ago . However, at that time, technology was not yet ready for introduction on a wider scale into the clinic. Short-term observations in a limited number of patients confirmed that BAT could reduce blood pressure and heart rate but long-term data yielded equivocal results. No randomized controlled trials with the devices have been done at that time so that the true value of the technique remained enigmatic. Due to the introduction of a variety of antihypertensive drugs that were well tolerated, there was less and less need for invasive procedures and the further development of devices for BAT was considerably delayed for a long period of time .

Since the beginning of the twenty-first century, new devices with improved technology are available. So far, the most important of these and the ones that have been tested clinically are the Rheos^TM Baroreflex Hypertension Therapy System and its successor, the Barostim neo ^TM device. These are open-loop systems with electrodes that are attached surgically to the carotid artery at close proximity to the bifurcation. While the Rheos device still worked through bilateral stimulation, the other one has been designed for unilateral implantation and stimulation. The devices further consist of an implantable pulse generator and an external programmer.

The Rheos device was initially tested intra-operatively in patients who needed elective carotid artery surgery [8]. Baseline blood pressure of these patients was 146 ± 30 mmHg systolic and 66 ± 17 mmHg diastolic. When blood pressure and heart rate had stabilized, the investigators constructed some kind of dose–response curve by applying incrementally increasing electrical currents. Blood pressure and heart rate fell significantly in a voltage-dependent way by, on average, 23 mmHg systolic and 16 mmHg diastolic. These observations paved the way for application of the device in patients with difficult-to-treat hypertension .

The Device-Based Therapy in Hypertension (DEBuT-HT) Trial was the first multicentre, prospective, nonrandomized feasibility study to assess safety and efficacy of the Rheos system over a period of 3 months in treatment-resistant hypertensive patients [9]. Treatment resistance was defined as a blood pressure equal or above 160/90 mmHg despite treatment with at least three antihypertensive agents, including a diuretic. Secondary hypertension and nonadherence to treatment had to be excluded. Patients who qualified for the study had the baropacer implanted (bilaterally) but to allow undisturbed tissue healing, the device was not activated until 1 month after the surgical procedure. To avoid a confounding effect of medication, drug dosages had to remain constant during the 3 months of the study that the device was on. Altogether, 45 patients entered this trial. Their mean age was 54 years and their blood pressure 179 ± 29 mmHg systolic and 105 ± 22 mmHg diastolic. At the end of the 3-month period with the device on, blood pressure had fallen significantly by an average of 21/12 mmHg. Although a few side effects were noted, by and large the safety profile was favorable [9]. Thus, the study showed that it is possible to lower blood pressure in patients with drug-resistant hypertension by modulating baroreceptor function without major adverse events. It is also very likely that the effectiveness of the device relates to its potential to reduce sympathetic traffic in the body. Indeed, when intra-arterial blood pressure and muscle nerve sympathetic activity (MSNA) were recorded simultaneously in 12 patients who had the baropacing system implanted, electrical stimulation caused a sharp fall not only in pressure but also in MSNA [10]. In the responders, the decrement in pressure correlated with the fall in MSNA. Throughout the stimulation period, MSNA remained below baseline levels. Switching the device off was associated with reversal of these effects .

Several patients who had participated in DEBuT-HT could be followed for a longer period of time. Over the years, they maintained their blood pressure reduction and it was even possible to withdraw some of their medication [11]. However, since DEBuT-HT was an uncontrolled feasibility and proof-of-principle trial, it did not have the power to prove unequivocally that BAT is beneficial in resistant hypertension. Therefore, the Rheos Pivotal Trial was designed as a randomized, double-blind, parallel-design clinical trial comparing immediate and delayed BAT. It included 265 patients with resistant hypertension (average baseline blood pressure 178/103 mmHg) over a period of 6 months who were randomized in a 2:1 ratio to either immediate activation of the device (i.e., 1 month after the implant, group A) or delayed activation (7 months after the implant, group B). Thus, the second, smaller group could be considered as a sham-operated or placebo group in this respect. The trial had five primary outcome variables related to efficacy and safety at 6 months of stimulation [12]. After the 6-month assessment, the baropacer was switched on in patients from group B as well and 6 months later all measurements were repeated. Although the drop in pressure was numerically greater with the device on, the difference in responder rates between both groups at 6 months was smaller than the prespecified primary efficacy end point of 20 %. Thus, in this randomized trial, baropacing was not more effective than sham operation during a period of 6 months. Possibly, the placebo effect and the effect of participating in a trial were greater than anticipated . Nevertheless, the proportion of patients who reached the goal pressure of 140 mmHg systolic or below (a secondary end point) was greater in group A (42 vs. 24 %; p <↔0.005). Moreover, at 12 months when all patients had the device on, the two groups showed a comparable drop in blood pressure as compared to baseline. No major safety concerns were encountered and only short-term procedure-related adverse events were seen, most of which disappeared after some time [12]. After the formal part of the trial, patients were followed for more than 2 years [13]. The vast majority of these patients continued to exhibit lower blood pressures and among the responders to BAT the number of prescribed medications could be reduced by 1–2 classes.