157resistant hypertension such as obesity, metabolic syndrome, and renal disease, a
direct mechanistic link between the angiotensin II and sympathetic activation is not
clear-cut. An emerging area of investigation is the activation of the central nervous
system proopiomelanocortin-melanocortin 4 receptor (MC4R), a major regulator of
appetite, energy expenditure, autonomic nervous system activity, and cardiovascu-
lar response to stress. In addition to mechanistic insight from experimental studies,
the observation that MC4R deficiency in humans is associated with a lower preva-
lence of hypertension and lower blood pressure levels [ 35 ] provides support for the
concept that the proopiomelanocortin-MC4R pathway may contribute to chronic
sympathetic activation and hypertension [ 33 , 35 ].
Non-pharmacological Suppression of Sympathetic Activity
in Hypertension
Bearing on the relatively high, although not yet clearly established, incidence of
resistant hypertension and the clear evidence of excessive sympathetic drive not
only as powerful mediator of hypertension but also as mitigator of the antihyperten-
sive effects of pharmacological therapies, intensive efforts have been recently
directed toward the development of non-pharmacological sympathoinhibitory
approaches. Of these, baroreflex activation therapy (BAT) and catheter-based radio-
frequency renal nerve ablation have quickly reached technological maturity and
stand nowadays the test of clinical efficacy [ 1 , 4 , 36 ].
Baroreflex Activation Therapy
The modern technology of BAT has overcome the limitations of the early attempts
at electrical stimulation of the carotid baroreflex. The present system developed by
CVRx Inc. has the capability of delivering electrical energy directly at the carotid
sinus, through electrodes implanted in the perivascular space rather than the carotid
sinus nerve, as in previous studies [ 4 , 37 ]. This approach has the advantage of avoid-
ing damage to the sinus nerve and also preventing concomitant activation of fibers
carrying chemoreflex afferent signals from the carotid body. As noted above, activa-
tion of the carotid chemoreflex would provide a powerful sympathoexcitatory drive
[ 31 ] thus limiting the efficacy of baroreflex activation. Furthermore, the electrode
design of the current system virtually eliminates problems related to extraneous
nerve and muscle stimulation seen in earlier studies, while the implantable minia-
ture pulse generator allows externally programmable and controlled delivery of cur-
rent throughout the day.
After a successful first-in-human proof-of-concept study of the first-generation
Rheos (CVRx Inc.) system the Device-Based Therapy in Hypertension Trial
10 Secondary Causes: Work-Up and Its Specificities in CKD: Influence of Autonomic...