resistant hypertension is defined as blood pressure remaining above the target value in spite of the concurrent use of three antihypertensive agents of different classes . ideally , one of the three agents should be a diuretic and all agents should be prescribed at optimal dose amounts . while the exact prevalence of resistant hypertension is unknown , clinical trials suggested that it is not rare , involving about 20 - 30% of all study participants . a carotid sinus is a dilated area located in the bifurcation of the carotid artery . it contains numerous baroreceptors , which are stretch - sensitive mechanoreceptors and innervated by the carotid sinus nerve . carotid sinus baroreceptors are sensitive baroreceptors that can sense the intra - arterial blood pressure change and regulate the sympathetic tone towards the opposite direction ( as a negative feedback ) . when blood pressure is elevated , carotid baroreceptors are activated to send signals to the brain stem nuclei in which inhibitory signals are delivered to attenuate the sympathetic tone and subsequently the blood pressure after a complex signal reception and conversion process . the idea of stimulating carotid baroreceptors as an approach to lower blood pressure is not new . more than a century ago , cooper   uncovered the roles of the baroreceptor system in regulating blood pressure . it was demonstrated that in animals , the blood pressure decreased when the carotid sinus nerve was electrically stimulated , while it increased if the nerve was transected . in 1965 , the pioneering work by bilgutay and lillehei   utilized a compact implantable device with two electrodes attached directly to the carotid sinus of seven hypertensive dogs . the results indicated that bilateral electrical stimulation of the baroreceptors for 2 h caused a drop in blood pressure , with a reduction in systolic blood pressure ( sbp ) ranging from 35 to 100 mm hg and from 25 to 75 mm hg in diastolic blood pressure . one year later , they employed this technique in 2 patients : 1 had a blood pressure reduction from 250/160 to 130/90 mm hg and the other from 280/160 to 140/100 mm hg . clinical studies demonstrated that the mechanism of resetting and the insensitivity of the baroreceptor system contributed to the elevated blood pressure in hypertensive patients . these data indicated that the primary function of the baroreceptor system was to balance the sympathetic and vagal tone , thereby regulating blood pressure . unfortunately , at that time , the baroreflex was regarded as a short - term regulation system with temporal effects . this recognition , together with adverse effects , discouraged further investigation of carotid baroreceptor stimulation as a potential treatment for hypertension . recently , with the accumulation of knowledge on baroreflex and technical progress , treating resistant hypertension with carotid baroreceptor stimulation has emerged and been popularized . results from recent studies have suggested that the baroreflex also exerts a long - time control on the sympathetic output and participates in the balance of body fluid volume regulated by kidney , and is thus involved in the long - term regulation of blood pressure . in 2004 , lohmeier et al .   showed that prolonged bilateral stimulation of carotid baroreceptors in conscious dogs could reduce blood pressure and heart rate significantly for 7 days . the first clinical study evaluating the efficacy and safety of carotid baroreceptor stimulation for long - term treatment of hypertension was performed in 2004 . a hypertensive patient with several implantable devices for carotid baroreceptor stimulation have been developed , which facilitates research in this field . , usa ) consists of an implantable pulse generator , two electrode leads attached to the carotid sinus and an external programming system . the pulse generator delivers activation energy ( voltage range 1 - 7.5 v ) through electrode leads to stimulate the carotid sinus , and then the triggered baroreceptors send signals to the brain , which are interpreted as a rise in blood pressure . the brain initiates the body 's own control mechanisms to counteract this perceived rise in blood pressure by delivering signals to other parts of the body to reduce blood pressure . in their study , heusser et al . have shown that the depressor response was achieved through sympathetic inhibition , together with a decrease of the heart rate . moreover , there was a correlation between depressor response and the reduction of muscle sympathetic nerve activity . after implantation , the device should not be switched on until the patients recover for 1 month . then , they should undergo a dose - response test and parameter settings ( typically 100 hz of continuous bilateral stimulation , < 7 v ) to obtain an optimal antihypertensive efficacy . several influential studies have evaluated the efficacy and safety of carotid baroreceptor stimulation in the short - time and long - time control of blood pressure . in a phase ii feasibility trial , 10 patients with resistant hypertension ( sbp 160 mm hg ) were enrolled and successfully underwent bilateral implantation of the rheos system . as the voltage increased , the mean sbp decreased from 170 to 133 mm hg in an intraoperative test and from 180 to 139 mm hg before hospital discharge . moreover , it revealed a linear relationship between voltage value and hemodynamic response ( r = 0.88 ) , with the maximal response observed at around 4.8 v. there were no unanticipated serious adverse events ( saes ) throughout the trial process . the rheos system has proven to be safe and effective in the treatment of resistant hypertension . the debut - ht ( device based therapy in hypertension trial ) was a multicenter , prospective , nonrandomized feasibility study . the study aimed to evaluate the safety and efficacy of the rheos system over 3 months or longer in patients with resistant hypertension . compared to the baseline mean blood pressure ( 179/105 mm hg ) , there was a mean reduction of 21/12 mm hg . during the 1-year and 2-year follow - ups , the mean blood pressure was reduced by 30/20 and 33/22 mm hg , respectively . in terms of safety , 7 subjects experienced procedure - related saes , and 1 subject experienced device - related saes . none of the patients suffered carotid artery stenosis during the follow - up period . during the trial , a substudy of voltage - dependent blood pressure response was conducted at the same time . the voltage response test was performed at 1 , 4 , and 13 months after implantation . by comparing the index of the baroreflex sensitivity this indicated that the baroreflex function was preserved 1 year after the stimulation , and there was no response adaption or nerve fatigue . the rheos pivotal trial was a prospective , double - blind , randomized , multicenter , placebo - controlled phase iii clinical trial to evaluate the efficacy and safety of the rheos device in patients with resistant hypertension . a total of 265 subjects implanted with the device were randomized ( 2:1 ) into two groups . group a ( n = 181 ) initiated the therapy immediately ( the device was activated 1 month after implantation ) and group b ( n = 84 ) received the therapy 6 months later ( the device was activated 7 months after implantation ) . the trial was designed to demonstrate five primary end points during 12 months of follow - up . the results indicated that the trial did not reach two of the five end points in procedure safety and short - time efficacy . procedure safety was evaluated by the incidence of adverse events related to the implantation procedure itself within the first 30 days . it showed an event - free rate of 74.8% , which was less than the prespecified target value of 82% . the acute efficacy end point was judged by measuring the proportion of subjects in the two groups that obtained a drop of sbp by at least 10 mm hg within the first 6 months . the results indicated that 54% of subjects in group a and 46% in group b reached the level . with a superiority margin of 20% that was set for this end point , apart from these , the other three end points were successfully reached in this study , including 12-month efficacy , carotid baroreceptor stimulation safety and device safety . a secondary analysis indicated that 42% of patients in group a achieved the target blood pressure ( sbp 140 mm hg ) at the 6-month evaluation , while only 22% of patients in group b achieved this level ( p = 0.005 ) . this study showed that 63% of subjects reached the target sbp of 140 mm hg , and 81% of subjects achieved a minimum of 10 mm hg reduction after implantation . thereafter , the subjects consented to participate in a longer , nonrandomized follow - up lasting from 22 to 53 months . during the follow - up , the mean blood pressure was reduced by 35/16 mm hg , and 55% of subjects achieved the target blood pressure . the results have revealed an even longer control of blood pressure through carotid baroreceptor stimulation . to facilitate the operational process of the device implantation , the barostim neo system , compared to the previously developed rheos system , the barostim neo system consists of one pulse generator , one lead electrode directly sutured to the unilateral carotid sinus and a laptop computer - based programming system . the carotid sinus electrode serves as cathode ( 6 mm in diameter ) , while the pulse generator acts as anode . in an open - label , nonrandomized study of 30 resistant hypertensive patients implanted with the barostim neo system , blood pressure averagely the results were comparable to those in the debut - ht   and rheos pivotal trial using the rheos system . the percentage of patients achieving an sbp of < 140 mm hg reached 43% , consistent with that in the rheos pivotal trial ( 42% ) . therefore , the second - generation system can significantly lower blood pressure , with similar efficacy compared to the rheos system . in terms of safety , up to 90% of patients were free from system- or procedure - related adverse events within the first 30 days after implantation . a similar result ( 88% ) was achieved in a study on short - time cardiac pacemaker implantation . during long - time observation ( > 180 months ) furthermore , implantation process time decreased from 198 min with the rheos system to 107 min with the second - generation system due to the unilateral exposure of the carotid sinus . the second - generation , minimally invasive system has preliminarily demonstrated its safety and efficacy in the treatment of resistant hypertension , and a large , randomized controlled trial is currently being planned in full swing in north america for further study . carotid baroreceptor stimulation has been demonstrated to have great potential for treating resistant hypertension . however , this therapy is not suitable for all types of hypertension ( e.g. angiotensin ii - induced hypertension ) . in some previous trials , therefore , at present , it is still not possible to free patients completely from medication treatment by the carotid baroreceptor stimulation . all present devices depend on an external computer - controlled system rather than an in vivo closed - loop feedback system . thus , further studies are warranted to probe the mechanism of blood pressure regulation and to develop self - regulating devices with a closed - loop feedback .
resistant hypertension indicates that the blood pressure can not reach the target value despite standard drug treatment , which harbors an increased risk for cardiovascular diseases . 
 the role of the carotid sinus in regulating blood pressure has long been observed ; thereby , the idea that treating resistant hypertension by stimulating carotid baroreceptors emerged . 
 nevertheless , this idea has been abandoned for years due to technical limitations . 
 recently , with the evolutions in implantable electrical devices , expectations for treating resistant hypertension with baroreceptor stimulation have increased . 
 positive results from several multicenter clinical trials further captured the researchers enthusiasm for more effective baroreceptor - stimulating devices . 
 this study reviews the recent progress in baroreceptor stimulation as a treatment alternative for resistant hypertension .