Chronic effects of baroreflex activation therapy: a tale of the unexpected

Resetting of the baroreflex is a common phenomenon in sustained hypertension and indicates that the baroreceptor response diminishes with a new threshold for activation [1]. Therefore, it is unsurprising that researchers have sought ways to treat hypertension by modulating the baroreflex system. Carlsten et al.[2] were the first to report the effects of carotid sinus stimulation in man. In five patients who underwent surgery for neck cancer, a prompt decrease in blood pressure and heart rate was observed when the carotid sinus nerve was stimulated with a bipolar electrode. Over the following two decades, several investigators have confirmed the potential of electrical activation of the baroreceptor system in the treatment of hypertension [3]. However, further developments were halted, largely because of the introduction of new drugs, which made it much easier to treat patients with hypertension. Still, a sizeable proportion of patients appear to be resistant to various antihypertensives, a condition that is associated with marked sympathetic activation [4]. Fortunately, at the beginning of this century, renewed interest in the role of baroreceptor activation therapy (BAT) arose with the development of a new device, the Rheos system (CVRx, Inc., Minneapolis, Minnesota, USA). This consisted of an implantable pulse generator (IPG), two electrical leads applied around both carotid sinuses and an external programmer. After Schmidli et al.[5] tested the system in patients undergoing elective carotid artery surgery, our group found a decrease in blood pressure of 21/12 mmHg after 3 months in 45 patients in whom the device had been implanted and 33/22 mmHg in 17 patients who completed 2 years of follow-up [6]. However, this study was uncontrolled, and the changes in ambulatory blood pressure were far less impressive. Subsequently, the Rheos pivotal trial was designed as a double-blind, randomized, prospective, multicenter, placebo-controlled study in patients with treatment-resistant hypertension [7]. Although this trial showed a significant benefit for the endpoints of sustained efficacy, it did not meet the endpoints of acute responses or procedural safety. In retrospect, this trial could be criticized for not having defined appropriate endpoints, but the message that came across widely was disappointing efficacy. It has also paved the way for the implementation of alternative treatments, such as renal denervation (RDN). Although many enthusiastic investigators were willing to set up new, well designed trials, the company that manufactured the Rheos system unexpectedly decided not to pursue this further. Instead, another device was launched: the Barostim neo. This device has a smaller IPG and only one stimulation electrode attached to either the left or right carotid sinus. This second-generation device also lowers blood pressure, even in patients with prior RDN [8]. However, there have been no randomized trials with Barostim neo in hypertension, and these are not expected either. As an alternative to demonstrate its efficacy, blood pressure responses to deactivation and activation of BAT can be monitored. In this issue of the Journal, a group of German investigators who have worked with the device for years reported on such data in patients who had the device implanted between 2011 and 2017 [9]. Sixteen patients who were scheduled for device replacement randomly switched the device off for 4 weeks and then on again for 4 weeks or left the device on and switched if off 4 weeks later. The study failed to show an appreciable effect on office blood pressure, but home blood pressure increased significantly after deactivation of the BAT-neo. What does this mean? The increase in home blood pressure was extremely small (on average only 5/3 mmHg), and we cannot rule out that this is a chance finding, especially as an earlier study with a comparable approach did not find an effect of deactivation on home blood pressure [10]. With such small increments, it is not surprising that changes in office blood pressure were not significant, even though the systolic pressure tended to increase. Ambulatory blood pressure measurements would probably have provided a better insight into the true blood pressure patterns; however, for logistical reasons, they were not implemented by the investigators. Perhaps more relevant and intriguing is the fact that blood pressure did not ‘jump back’ to its original level, that is the level before implantation. This unexpected finding is in sharp contrast with the immediate and often large pressure changes seen in patients who have undergone BAT for a relatively short period of time [11,12]. From the available data, it now seems that the longer the patients are exposed to BAT, the smaller the pressure rise upon deactivation of the device, and the same is true for changes in heart rate. This is certainly not compatible with chronic tonic inhibition of sympathetic outflow by BAT. While these data suggest that continued BAT resets the baroreflex setpoint towards a lower level of blood pressure, they hint at the same time at decreased sensitivity for afferent input signals. The latter could be due, for instance, to scarring at the site of implantation or some form of nerve traffic exhaustion due to continuous afferent stimulation. Therefore, it is unfortunate that the investigators did not perform autonomic function tests together with measurements of catecholamines and/or muscle sympathetic outflow to further examine this. It would also be interesting to know whether carotid baroreceptor sensitivity returns to preimplantation levels if the device is switched off for a longer period. If the carotid baroreceptor system becomes less sensitive to normal pressure fluctuations following prolonged continuous electrical stimulation, the acute buffering of blood pressure changes will become more dependent upon the aortic baroreceptors. However, even with impairment of the carotid baroreceptor system, one would expect marked variability in blood pressure, which is usually not observed in chronic BAT. This area deserves further scrutiny if BAT is to be used as a treatment option for hypertension. Unfortunately, and again unexpectedly, the company has lost interest in hypertension and now focuses primarily on the use of the device in patients with heart failure [13]. While this is certainly a legitimate choice from a managerial perspective, it deprives many hypertensive patients of a therapy that could potentially be lifesaving. One may argue that RDN is an acceptable alternative; however, unlike RDN, BAT has the advantage that it remains possible to individually adjust the stimulation parameters and, thereby, the degree of blood pressure reduction. Nevertheless, almost 70 years after the first electrical stimulation of the carotid sinus in humans, BAT remains in square one. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.