Download Baroreceptor stimulation for resistant hypertension

Archives of Cardiovascular Disease (2014) 107, 690—696
Available online at
ScienceDirect
www.sciencedirect.com
REVIEW
Baroreceptor stimulation for resistant
hypertension: First implantation in France
and literature review
Stimulation des barorécepteurs carotidiens comme traitement de
l’hypertension artérielle : premier cas en France et revue de la
littérature
Pierre-Yves Courand a,b,c,∗, Patrick Feugier b,c,d,
Stéphane Workineh e, Brahim Harbaoui a,
Giampiero Bricca b,c, Pierre Lantelme a,b,c
a
Cardiology Department, European Society of Hypertension Excellence Centre, Hôpital de la
Croix-Rousse, Hospices Civils de Lyon, Lyon, France
b
Génomique Fonctionnelle de l’Hypertension Artérielle, EA 4173, Université Claude-Bernard
Lyon 1, Villeurbanne, France
c
Hôpital Nord-Ouest, Villefranche-sur-Saône, France
d
Vascular Surgery Department, Hôpital Edouard-Herriot, Hospices Civils de Lyon, Lyon, France
e
Anaesthesia Department, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
Received 1st July 2014; received in revised form 28 August 2014; accepted 29 August 2014
Available online 16 October 2014
KEYWORDS
Baroreflex;
Baroreceptor
activation therapy;
Sympathetic nervous
system;
Resistant
hypertension
Summary Despite a wide choice of effective antihypertensive treatments, blood pressure
(BP) in roughly half of hypertensive subjects is not controlled. Resistant hypertension is defined
as an uncontrolled BP despite optimal doses of three antihypertensive treatments, including a
diuretic. After confirmation of resistant BP using home BP measurement or 24-hour ambulatory
BP monitoring (ABPM), patients usually go through a work-up to rule out secondary hypertension. If secondary hypertension is ruled out, the recent European guidelines on hypertension
consider baroreceptor stimulation or renal denervation to be possible options. The prevalence of resistant primary hypertension may reach up to 10% in specialized centres. The two
proposed non-pharmacological therapeutic strategies have been developed recently to inhibit
Abbreviations: ABPM, ambulatory blood pressure monitoring; BAT, baroreceptor activation therapy; BP, blood pressure; CT, computed
tomography; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure.
∗ Corresponding author. Cardiology Department, European Society of Hypertension Excellence Centre, Hôpital de la Croix-Rousse, Hospices
Civils de Lyon, 103, Grande-Rue-de-la-Croix-Rousse, 69004, Lyon, France.
E-mail address: [email protected] (P.-Y. Courand).
http://dx.doi.org/10.1016/j.acvd.2014.08.002
1875-2136/© 2014 Elsevier Masson SAS. All rights reserved.
Baroreceptor stimulation for resistant hypertension
691
sympathetic overactivity in resistant hypertension. Among them, baroreceptor activation therapy (BAT) is an innovative approach that interferes with baroreflex function. The first-generation
BAT device (Rheos® ; CVRx, Inc., Minneapolis, MN, USA) demonstrated good efficacy in lowering
office BP and ABPM, but had an insufficient safety profile due to complex surgery. The secondgeneration BAT device (Barostim neoTM system; CVRx, Inc.) seems to share the same BP-lowering
efficacy but has a better safety profile. We report the first French case of baroreceptor stimulation for hypertension using the Barostim neoTM system. We also discuss the pathophysiological
features of and current levels of evidence for this technique.
© 2014 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS
Baro-réflexe ;
Traitement activateur
des barorécepteurs ;
Système nerveux
sympathique ;
Hypertension
artérielle résistante
Résumé Malgré la disponibilité de nombreuses classes d’anti-hypertenseurs, la moitié des
patients hypertendus ne sont pas contrôlés. L’hypertension résistante se définit par une pression artérielle non contrôlée malgré l’utilisation de trois anti-hypertenseurs à doses optimales
dont un diurétique. Après confirmation par auto-mesures ou holter tensionnel, les patients
ayant une hypertension résistante doivent bénéficier d’un bilan complet à la recherche de
formes secondaires. La prévalence de l’hypertension essentielle résistante est de l’ordre de
5 à 10 % dans les centres spécialisés. Les recommandations européennes proposent la stimulation des barorécepteurs ou la dénervation rénale en cas d’hypertension non contrôlées par
les mesures pharmacologiques. Ces deux approches non pharmacologiques ont été développées
récemment pour cibler l’hyperactivation du système nerveux sympathique dans l’hypertension
artérielle résistante. La stimulation des barorécepteurs carotidiens est une approche innovante
ciblant la régulation du baro-réflexe. La première génération de stimulateur des barorécepteurs (Rheos® ; CVRx, Inc., Minneapolis, MN, États-Unis) a démontré une bonne efficacité en
termes de baisse de pression artérielle, cependant les risques opératoires liés à la complexité
de la procédure étaient importants. La seconde génération de stimulateur des barorécepteurs
(le système Barostim neoTM ; CVRx, Inc.) semble démontrer une efficacité similaire en termes
de baisse de pression artérielle et un meilleur profil de sécurité en raison d’une procédure
d’implantation plus simple. Nous présentons le premier cas français d’implantation d’un stimulateur des barorécepteurs avec le système Barostim neoTM . Nous décrivons également les
aspects physiopathologiques et le niveau de preuve actuel de la technique.
© 2014 Elsevier Masson SAS. Tous droits réservés.
Background
Despite a wide number of antihypertensive treatments,
roughly half of hypertensive subjects are not controlled
[1]. The therapeutic strategy for managing resistant hypertension has been simplified recently in the latest French
guidelines [2]. Resistant hypertension is defined as an uncontrolled blood pressure (BP) despite optimal doses of three
antihypertensive treatments, including a diuretic. Resistant
office BP must be confirmed using home BP measurement
or 24-hour ambulatory BP monitoring (ABPM). When resistant hypertension is confirmed, patients undergo a work-up
to rule out secondary hypertension. This may leave up to
10% of true resistant primary hypertension in dedicated
centers accustomed to the management of hypertension
in France [3—5]. These patients may be considered for
a non-pharmacological approach (i.e. renal denervation).
While this technique appeared very promising after the
SYMPLICITY HTN-1 and HTN-2 trials, the publication of
the SYMPLICITY HTN-3 trial has cast some doubt on its
real efficacy [6—8]. In addition, there are some limitations
related to renal function (estimated glomerular filtration
rate < 45 mL/min) and renal artery anatomy (length and
diameter before bifurcation, accessory renal arteries) that
preclude its use in every resistant patient. Thus, there is
still room for other approaches in this currently unsettled
field.
One alternative (or additional) approach could be
baroreceptor stimulation — a novel technique targeting the
baroreflex via stimulation of the carotid sinus wall [9].
The recent European guidelines on hypertension made the
following recommendations: to consider baroreceptor stimulation or renal denervation in case of ineffectiveness of
drug treatment in patients with resistant hypertension (class
IIb, level C) and, until more evidence is available on the
long-term efficacy and safety of renal denervation and
baroreceptor stimulation, to restrict these procedures to
hypertension centers (class I, level C) [10].
We report here on the first French implantation of a
baroreceptor stimulator for hypertension, and we discuss
the pathophysiological features of and current levels of evidence for this technique.
Case report
A 74-year-old man was referred to our department for an
arterial hypertension work-up. His medical history included
692
P.-Y. Courand et al.
Figure 1. Implantation procedure. (A) Right carotid sinus exposure. (B) Positioning of the electrode around the bifurcation in the area of
the carotid sinus. (C) Decrease in blood pressure during activation of the generator.
peripheral artery disease (bypass graft and angioplasty),
single-vessel coronary artery disease treated with a baremetal stent on the left anterior descending artery, with
a left ventricular ejection fraction (LVEF) of 55% and
obstructive sleep apnea syndrome treated with continuous
positive airways pressure. After withdrawal of antihypertensive treatment interfering with hormonal status, we
ruled out secondary endocrine forms of hypertension (mainly
primary aldosteronism, Cushing’s syndrome and pheochromocytoma). Duplex ultrasound did not demonstrate any
significant renal artery stenosis. Target organ damage
was observed at the level of the heart (left ventricular mass index 155 g/m2 ), vessels (pulse wave velocity
16 m/s) and kidney (estimated glomerular filtration rate
49 mL/min and microalbuminuria 280 mg/24 hours). Antihypertensive treatment was gradually optimized and a low
dose of spironolactone was not tolerated because of hyperkalemia. Finally, the patient received daily: indapamide
1.5 mg, amlodipine 10 mg, valsartan 160 mg, nebivolol 5 mg,
rilmenidine 1 mg and prazosin 5 mg. ABPM was uncontrolled on supervised intake of drugs: 172/75 mmHg,
24 hours; 172/76 mmHg, daytime; and 172/72 mmHg, nighttime (non-dipper status). Long-term non-compliance with
antihypertensive treatment was unlikely using questionnaires and home BP measurement. The patient was first
screened for renal denervation. A computed tomography
scan demonstrated mild atherosclerotic stenosis of around
40% on both renal arteries and a right inferior accessory renal
artery. Moreover, we observed an occlusion of the superficial right femoral artery and an occlusion of the left bypass.
Renal denervation was not possible because of two exclusion
criteria: renal artery atheroma and severe peripheral artery
disease.
Carotid ultrasonography ruled out significant atherosclerosis (> 50% reduction in diameter). Baroreceptor stimulator
implantation was indicated. Twenty-four hours before
surgery, antihypertensive treatments that interfere with the
sympathetic nervous system were withdrawn (angiotensin
receptor blocker, diuretics and beta-blockers) and replaced
with a continuous intravenous infusion of nicardipine. The
level of the right carotid bifurcation was marked using
ultrasound guidance. General analgesia was performed
with specific drugs (etomidate, midazolam, fentanyl and
rocuronium) known for their limited interaction with the
sympathetic nervous system. A catheter was placed in the
left radial artery for continuous BP monitoring. The implantation procedure consisted of a right carotid sinus exposure
via a 4 cm incision (Fig. 1A). The electrode was positioned
around the bifurcation in the area of the carotid sinus
(Fig. 1B). The electrode and lead were connected to the battery impulse generator and briefly activated with impulses
of 3 V, 100 Hz and a pulse width of 480 micros, once blood
pressure and heart rhythm were stable. The hemodynamic
response was tested and the electrode was repositioned in
different locations to identify the site of optimal response.
A marked acute reduction in BP was observed from 171/64
to 119/45 mmHg (Fig. 1C). Once the optimal location was
confirmed, the electrode was sutured in place; then, a subcutaneous pocket was made inferior to the right clavicle
for the battery impulse generator (Barostim neoTM system;
CVRx, Inc.). The lead was advanced under the skin and connected to the battery (Fig. 2). The battery impulse generator
was sutured in place with a permanent suture, and the
two incisions were closed in layers with absorbable sutures.
All antihypertensive treatments were started 24 hours after
surgery, and the patient was discharged from hospital on the
third day after device implantation.
Baroreflex activation therapy (BAT) was initiated only
2 weeks after implantation. Programmed variables (pulse
amplitude, pulse width and frequency) were titrated
for optimal response over the first few months. Trained
CVRx field staff performed device programming under the
Baroreceptor stimulation for resistant hypertension
Figure 2.
693
Implantation procedure: subcutaneous pocket for the battery impulse generator and tunnel for connecting the lead.
direction of the clinician. Prazosin was withdrawn after
initiation of the therapy because of orthostatic hypotension.
BAT was well tolerated, with only a transient episode of
cough and hoarseness when a high intensity of stimulation
was used. After 9 months of follow-up, we observed a reduction of 15 mmHg in SBP and a reduction of 8 mmHg in DBP
on 24-hour ABPM (157/67 mmHg, 24 hours; 158/67 mmHg,
daytime; and 155/66 mmHg, night-time), with five antihypertensive drugs: indapamide 1.5 mg; amlodipine
10 mg; valsartan 160 mg; nebivolol 5 mg; and rilmenidine
1 mg.
Pathophysiological effects of sympathetic
activity in hypertension
Different mechanisms are involved in the pathogenesis of
hypertension and particularly in resistant hypertension: the
renin-angiotensin-aldosterone system, the kidneys, and the
sympathetic nervous system. Sympathetic overactivity has
been associated with increased BP and also with a high incidence of target organ damage: left ventricular hypertrophy,
renal failure, and hypertensive retinopathy [11,12]. Pharmacological agents (beta-blockers, alpha-blockers, centrally
acting drugs) and, more recently, non-pharmacological
therapeutics (renal denervation, baroreceptor stimulation)
have been developed to inhibit sympathetic overactivity in
hypertension (Fig. 3). Baroreflex regulation originates from
baroreceptors located in the aortic arch and carotid sinuses.
Baroreceptors are mechanoreceptors that are activated by
pressure-induced stretch on the vessel wall. Baroreceptor
afferents from the carotid sinus travel in the carotid sinus
nerve before joining the glossopharyngeal nerve (IX), while
those from the aortic arch travel in the vagus nerve (X).
All baroreceptor afferents terminate in the nucleus of the
tractus solitarius in the medulla of the brain. Efferents of
the central nervous system are represented by sympathetic
fibres for the heart and vessels, but also by parasympathetic
fibres only for the heart. The sympathetic and parasympathetic tones allow tight control of BP in the short-term
(Fig. 4).
Alteration of the baroreflex is a common phenomenon
in chronic hypertension. Indeed, a sustained BP elevation
implies a diminished baroreceptor response; this is known
as baroreflex resetting and corresponds to a new threshold
of baroreceptor activation [13]. Baroreceptor stimulation
seems to be an innovative approach to restore this pathophysiological feature in hypertensive subjects.
Current level of evidence for
baroreceptor stimulation
Resistant hypertension
The original implantable active medical BAT device (Rheos® ;
CVRx, Inc., Minneapolis, MN, USA) activates the carotid
baroreflex through electrical stimulation of the walls of both
carotid sinuses (Fig. 5). Both electrodes implanted on the
exterior surface of the carotid sinus wall are connected to
a battery-powered impulse generator. This concept was initially validated in animal studies. In conscious dogs, 7 days
of baroreflex activation demonstrated a sustained reduction in heart rate, mean arterial BP and norepinephrine
concentration [14]. In the same animal model, a high continuous infusion of angiotensin II was associated with a lower
effect of baroreflex activation on BP [15]. In a dog model
of obesity-induced hypertension with a fatty diet, the same
team observed that baroreflex activation chronically suppressed the sympathoexcitation associated with obesity and
abolished the attendant hypertension [16].
The first-in-man feasibility of BAT was described in 2007
in 17 patients with drug-resistant hypertension (5.2 ± 1.8
antihypertensive drugs) enrolled in a European multicentre study [9]. These preliminary data suggested that the
procedure had an acceptable safety level, with a low rate
of adverse events: one hypoglossal nerve injury (symptoms
of hoarseness and eating disturbances), which improved
during follow-up, and one infection requiring complete
removal of the device. Overall, office blood BP fell by
28/16 mmHg. Three years later, Device Based Therapy in
Hypertension Trial (DEBuT-HT) — a multicentre prospective
non-randomized feasibility study to assess the safety and
efficacy of the Rheos® system over 3 months — was published
[17]. Forty-five patients with systolic BP (SBP) ≥ 160 mmHg
or diastolic BP (DBP) ≥ 90 mmHg despite at least three
antihypertensive drugs were enrolled, and were followed
up for as long as 2 years. After 3 months of BAT, the
mean office BP was reduced by 21/12 mmHg (P < 0.001)
and ABPM was reduced by 6/4 mmHg (P = 0.102). After 1
and 2 years of follow-up, the office BP fell by 30/20 mmHg
and 33/22 mmHg respectively (P < 0.002 for both). The
same trend was observed with ABPM, which decreased by
13/8 mmHg at 1 year and 24/13 mmHg at 2 years (P < 0.05
for all). Some serious adverse events were reported: three
infections requiring the device to be explanted; one perioperative stroke, probably due to intraoperative injury to the
hypoglossal nerve (tongue paresis without abnormalities on
694
Figure 3.
P.-Y. Courand et al.
Therapeutic targets of the sympathetic nervous system in hypertension.
brain magnetic resonance imaging); and one movement of
the implantable pulse generator, resulting in the need for
further surgery to reposition the implantable pulse generator.
In 2012, a double-blind randomized trial of 265 subjects
with resistant hypertension was performed [18]. All patients
were implanted and subsequently randomized (2:1) either to
group A with BAT for the first 6 months or to group B with
delayed BAT initiation following the 6-month visit. The trial
showed significant benefits for three of the five co-primary
endpoints: sustained efficacy (reduction in SBP of at least
10 mmHg at 12 months, 88% responders), BAT safety (40%
rate of reduction in hypertensive events in Group A), and
device safety (2.3% hypertension-related stroke). The two
other co-primary endpoints did not show significant benefit:
acute SBP responders at 6 months (achievement of 10 mmHg
fall in SBP compared with month 0, Group A 54%, Group B
46%; P = 0.97); and procedure safety (4.4% transient nerve
injury, 4.8% permanent nerve injury, 4.8% general surgical
complications and 2.8% respiratory complaint). The authors
concluded that significant and sustained reductions in SBP
were observed, but that new technology for delivering BAT,
which involves a less invasive implantation procedure, was
needed. Long-term follow-up of 22—53 months confirmed
the maintenance of the BP reduction [13].
A second-generation system for delivering BAT (Barostim
neoTM system; CVRx, Inc., Minneapolis, MN, USA) (Fig. 5),
with a simpler device and implantation procedure, has
been evaluated in a single-arm open-label study [19]. The
electrode portion of the lead consists of a single platinumiridium disc coated with iridium oxide and attached
concentrically to a circular insulative backer that is directly
sutured to the carotid sinus. The miniaturized electrode
and unilateral system design facilitate a minimally invasive implantation procedure. Thirty patients with resistant
hypertension were enrolled. With stable antihypertensive
treatment, office BP fell by 26/12 mmHg at 6 months and
the safety profile was similar to that for a pacemaker. During the perioperative period of 30 days after surgery, three
complications occurred: a self-inflicted wound complication; a pulse generator pocket hematoma; and discomfort in
the pulse generator pocket, requiring device repositioning.
A major limitation of this study was the absence of ABPM.
Thus, in resistant hypertension, BAT seems an option,
although the only randomized study did not reach its efficacy
endpoint; no comparable study with the second-generation
device is currently available. Many more data with this technique are thus required to validate its use. In addition, some
physiological features are far from being understood, including the fact that the BP response can be sustained while the
baroreflex is mainly involved in short-term BP regulation.
Another feature relates to the apparent lack of baroreceptor
downregulation — a common phenomenon observed in case
of chronic stimulation [20]. This new technique opens the
way for future research. Concerning clinical aspects, a multicentre French randomized trial is about to start; it will
Baroreceptor stimulation for resistant hypertension
Figure 4.
695
Regulation of blood pressure via the baroreflex.
events — are unknown. Sticking to the BP effect, the results
of SYMPLICITY HTN-3 trial on renal denervation have been
rather disappointing compared with previous SYMPLICITY trials [6—8,21]. The major information from this trial is the
placebo effect of this therapy, which was neglected in early
trials; this has to be taken into account in the same way as
for any medical treatment. Extensive use of ABPM, which
is less affected by the placebo effect than conventional BP
measurement, is highly desirable to assess the real effect of
these techniques. Another limitation is adherence to treatment; an advantage of the French DENER HTN study is that
it monitored this factor precisely. Obviously, when designing future trials on the Barostim neoTM system, these two
factors should be carefully considered.
Figure 5. First-generation and second-generation baroreceptor
stimulators.
evaluate the Barostim neoTM system compared with medical treatment alone, with special attention paid to safety,
benefit on ABPM and cost-effectiveness.
Perspectives
Baroreceptor stimulation and renal denervation are new
ways of treating hypertension. While these techniques are
extremely appealing, one has to recognize that their real
effects on BP — and, even more, on adverse cardiovascular
Other potential cardiovascular applications
Heart failure could be another application for BAT. Chronic
BAT has demonstrated enhancement of survival in dogs
with rapid pacing-induced heart failure [22]. In dogs
with coronary microembolization-induced heart failure, BAT
demonstrated an increase in LVEF and a partial reversal of LV
remodeling compared with a control group [23]. A randomized heart failure study involving 140 subjects is currently
underway. Patients were included with an LVEF < 35% and a
New York Heart Association Class III under optimal stable
heart failure therapy for at least 4 weeks, including cardiac
resynchronization therapy if indicated.
696
The effect of BAT on arrhythmias can be speculated upon,
given the major effect of beta-blockers. Further application
needs to be tested in this setting, such as severe ventricular
arrhythmia despite optimal treatment.
Conclusion
BAT is an innovative approach for treating resistant
hypertension via modulation of the baroreflex. The firstgeneration BAT device (Rheos® ) showed some effect on
BP in resistant hypertension, but its safety profile was
not satisfactory due to the complexity of the surgery.
The second-generation BAT device (Barostim neoTM system),
although it only applies stimulation to one carotid, has similar efficacy in terms of BP-lowering, with a good safety
profile, offering interesting perspectives. Further study is
needed to evaluate this latest device, and a French randomized trial will soon be launched.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
References
[1] Lantelme P. Blood pressure control: time for action. Arch Cardiovasc Dis 2009;102:465—7.
[2] Blacher J, Halimi JM, Hanon O, et al. [Management of arterial hypertension in adults: 2013 guidelines of the French
Society of Arterial Hypertension]. Ann Cardiol Angeiol (Paris)
2013;62:132—8.
[3] Courand PY, Dauphin R, Rouviere O, et al. [Renal denervation
for treating hypertension: first experience in Lyon]. Ann Cardiol
Angeiol (Paris) 2014;63:183—8.
[4] Rosenbaum D, Villeneuve F, Gury C, Girerd X. [Frequency
of hypertension resistant to treatment and indication for
renal denervation]. Ann Cardiol Angeiol (Paris) 2012;61:
229—33.
[5] Savard S, Frank M, Bobrie G, Plouin PF, Sapoval M, Azizi
M. Eligibility for renal denervation in patients with resistant hypertension: when enthusiasm meets reality in real-life
patients. J Am Coll Cardiol 2012;60:2422—4.
[6] Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial
of renal denervation for resistant hypertension. N Engl J Med
2014;370:1393—401.
[7] Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE,
Bohm M. Renal sympathetic denervation in patients with
treatment-resistant hypertension (The Symplicity HTN-2 Trial):
a randomised controlled trial. Lancet 2010;376:1903—9.
[8] Lantelme P, Courand PY, Pathak A. Renal denervation: a plea
for wisdom. Arch Cardiovasc Dis 2013;106:121—3.
P.-Y. Courand et al.
[9] Tordoir JH, Scheffers I, Schmidli J, et al. An implantable
carotid sinus baroreflex activating system: surgical technique
and short-term outcome from a multi-center feasibility trial for
the treatment of resistant hypertension. Eur J Vasc Endovasc
Surg 2007;33:414—21.
[10] Mancia G, Fagard R, Narkiewicz K, et al. 2013 Practice
guidelines for the management of arterial hypertension
of the European Society of Hypertension (ESH) and the
European Society of Cardiology (ESC): ESH/ESC Task Force
for the Management of Arterial Hypertension. J Hypertens
2013;31:1925—38.
[11] Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Mancia G.
Baroreflex control of sympathetic nerve activity in essential
and secondary hypertension. Hypertension 1998;31:68—72.
[12] Lambert E, Sari CI, Dawood T, et al. Sympathetic nervous
system activity is associated with obesity-induced subclinical
organ damage in young adults. Hypertension 2010;56:351—8.
[13] Navaneethan SD, Lohmeier TE, Bisognano JD. Baroreflex stimulation: a novel treatment option for resistant hypertension. J
Am Soc Hypertens 2009;3:69—74.
[14] Lohmeier TE, Irwin ED, Rossing MA, Serdar DJ, Kieval RS.
Prolonged activation of the baroreflex produces sustained
hypotension. Hypertension 2004;43:306—11.
[15] Lohmeier TE, Dwyer TM, Hildebrandt DA, et al. Influence
of prolonged baroreflex activation on arterial pressure in
angiotensin hypertension. Hypertension 2005;46:1194—200.
[16] Lohmeier TE, Dwyer TM, Irwin ED, Rossing MA, Kieval RS. Prolonged activation of the baroreflex abolishes obesity-induced
hypertension. Hypertension 2007;49:1307—14.
[17] Scheffers IJ, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension: results of
a European multi-center feasibility study. J Am Coll Cardiol
2010;56:1254—8.
[18] Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant
hypertension: results from the double-blind, randomized,
placebo-controlled rheos pivotal trial. J Am Coll Cardiol
2011;58:765—73.
[19] Hoppe UC, Brandt MC, Wachter R, et al. Minimally invasive system for baroreflex activation therapy chronically lowers blood
pressure with pacemaker-like safety profile: results from the
Barostim neo trial. J Am Soc Hypertens 2012;6:270—6.
[20] Bakris GL, Nadim MK, Haller H, Lovett EG, Schafer JE, Bisognano JD. Baroreflex activation therapy provides durable benefit
in patients with resistant hypertension: results of long-term
follow-up in the Rheos Pivotal Trial. J Am Soc Hypertens
2012;6:152—8.
[21] Lantelme P, Courand PY, Bricca G. Renal denervation in
hypertension: simplicity, or complexity? Arch Cardiovasc Dis
2014;107:421—3.
[22] Zucker IH, Hackley JF, Cornish KG, et al. Chronic baroreceptor
activation enhances survival in dogs with pacing-induced heart
failure. Hypertension 2007;50:904—10.
[23] Sabbah HN, Gupta RC, Imai M, et al. Chronic electrical
stimulation of the carotid sinus baroreflex improves left
ventricular function and promotes reversal of ventricular
remodeling in dogs with advanced heart failure. Circ Heart Fail
2011;4:65—70.