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198
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M. D. Lobo
Future Directions
Based upon the preclinical data and better understanding of
the role of the carotid body in the genesis and perpetuation of
neurogenic hypertension, carotid body ablation and/or carotid
sinus nerve denervation appear a worthwhile area of study.
The results from the single arm study described above are also
encouraging and support the need for larger randomised controlled trials in hypertensive patients in whom medicines
adherence is routinely assessed [25]. A key question to address
is whether single or bilateral CB ablation is necessary. On an
optimistic note, determination of baseline elevation of CB
drive using non-invasive methods intriguingly points towards
identication of those hypertensive patients who may be more
likely to respond to CB ablation therapy and may ultimately
help to rene the therapeutic selection process for device therapy of hypertension. A cautious approach is warranted given
the disruption to physiological ventilatory responses to
hypoxia that may ensue following CB ablation and also potential interruption of baroreex function.
However, future prospects for targeting the CB in the
treatment of hypertension do not appear bright: at the time
of writing the results of the transcatheter rst in man study
remain to be published in a peer reviewed journal.
Moreover, there are currently no active or forthcoming trials of carotid body denervation listed on ClinicalTrials.
gov and the company which manufactured the CB ablation catheter (Cibiem) is no longer operational with no
apparent competitor technologies currently on the
horizon.
Declaration of Interest Prof Lobo is a consultant to Medtronic, ReCor
Medical, Ablative Solutions, Aktiia and Vascular Dynamics. He has
received educational grants from Medtronic and ReCor Medical and
speaker fees from CVRx.
References
1. Iturriaga R. Translating carotid body function into clinical medicine. J Physiol. 2018;596(15):3067–77.
2. Marshall JM.Peripheral chemoreceptors and cardiovascular regulation. Physiol Rev. 1994;74(3):543–94.
3. Khan Q, Heath D, Smith P.Anatomical variations in human carotid
bodies. J Clin Pathol. 1988;41(11):1196–9.
4. Tan J, Xiong B, Zhu Y, Yao Y, Qian J, Rong S, etal. Carotid body
enlargement in hypertension and other comorbidities evaluated by
ultrasonography. J Hypertens. 2019;37(7):1455–62.
5. DiBona GF.The sympathetic nervous system and hypertension:
recent developments. Hypertension. 2004;43(2):147–50.
6. Despas F, Lambert E, Vaccaro A, Labrunee M, Franchitto N, Lebrin
M, etal. Peripheral chemoreex activation contributes to sympathetic baroreex impairment in chronic heart failure. J Hypertens.
2012;30(4):753–60.
7. Sobotka PA, Osborn JW, Paton JF. Restoring autonomic balance: future therapeutic targets. EuroIntervention. 2013;9(Suppl
R):R140-8.
8. Paton JF, Sobotka PA, Fudim M, Engelman ZJ, Hart EC,
McBryde FD, et al. The carotid body as a therapeutic target for
the treatment of sympathetically mediated diseases. Hypertension.
2013;61(1):5–13.
9. Lesske J, Fletcher EC, Bao G, Unger T. Hypertension caused by
chronic intermittent hypoxia—inuence of chemoreceptors and sympathetic nervous system. J Hypertens. 1997;15(12 Pt 2):1593–603.
10. Abdala AP, McBryde FD, Marina N, Hendy EB, Engelman ZJ,
Fudim M, etal. Hypertension is critically dependent on the carotid
body input in the spontaneously hypertensive rat. J Physiol.
2012;590(Pt 17):4269–77.
11. McBryde FD, Abdala AP, Hendy EB, Pijacka W, Marvar P, Moraes
DJ, et al. The carotid body as a putative therapeutic target for the
treatment of neurogenic hypertension. Nat Commun. 2013;4:2395.
https://doi.org/10.1038/ncomms3395. PMID: 24002774.
12. Roux JC, Peyronnet J, Pascual O, Dalmaz Y, Pequignot
JM. Ventilatory and central neurochemical reorganisation of O2
chemoreex after carotid sinus nerve transection in rat. J Physiol.
2000;522(Pt 3):493–501.
13. Serra A, Brozoski D, Hodges M, Roethle S, Franciosi R, Forster
HV. Effects of carotid and aortic chemoreceptor denervation in
newborn piglets. J Appl Physiol. 2002;92(3):893–900.
14. Hodges MR, Forster HV. Respiratory neuroplasticity following carotid body denervation: central and peripheral adaptations.
Neural Regen Res. 2012;7(14):1073–9.
15. Timmers HJ, Wieling W, Karemaker JM, Lenders JW.Denervation
of carotid baro- and chemoreceptors in humans. J Physiol.
2003;553(Pt 1):3–11.
16. Nakayama K.Surgical removal of the carotid body for bronchial
asthma. Dis Chest. 1961;40:595–604.
17. Winter B, Whipp BJ.Immediate effects of bilateral carotid body
resection on total respiratory resistance and compliance in humans.
Adv Exp Med Biol. 2004;551:15–21.
18. Trzebski A, Tal M, Zoltowski M, Przybylski J.Increased sensitivity of the arterial chemoreceptor drive in young men with mild
hypertension. Cardiovasc Res. 1982;16(3):163–72.
19. Sinski M, Lewandowski J, Przybylski J, Bidiuk J, Abramczyk P,
Ciarka A, etal. Tonic activity of carotid body chemoreceptors contributes to the increased sympathetic drive in essential hypertension. Hypertens Res. 2012;35(5):487–91.
20. Izdebska E, Cybulska I, Sawicki M, Izdebski J, Trzebski
A. Postexercise decrease in arterial blood pressure, total peripheral resistance and in circulatory responses to brief hyperoxia
in subjects with mild essential hypertension. J Hum Hypertens.
1998;12(12):855–60.
21. Narkiewicz K, Ratcliffe LE, Hart EC, Briant LJ, Chrostowska M,
Wolf J, etal. Unilateral carotid body resection in resistant hypertension: a safety and feasibility trial. JACC Basic Transl Sci.
2016;1(5):313–24.
22. Neuzil P, Reddy V, Malek F, Kmonicek P, Sievert H, Zeller T, etal.
Long term effect of transvenous carotid body ablation in the treatment of patients with resistant hypertension. Eur Heart J. 2017;38
23. Schlaich M, Schultz C, Shetty S, Hering D, Worthley S, Delacroix
S, etal. Transvenous carotid body ablation for resistant hypertension: main results of a multicentre safety and proof-of-principle
cohort study. Eur Heart J. 2018;39:267.
24. Mahfoud F, Bakris G, Bhatt DL, Esler M, Ewen S, Fahy M,
et al. Reduced blood pressure-lowering effect of catheter-based
renal denervation in patients with isolated systolic hypertension:
data from SYMPLICITY HTN-3 and the Global SYMPLICITY
Registry. Eur Heart J. 2017;38(2):93–100.
25. Mahfoud F, Azizi M, Ewen S, Pathak A, Ukena C, Blankestijn
PJ, etal. Proceedings from the 3rd European Clinical Consensus
Conference for clinical trials in device-based hypertension therapies. Eur Heart J. 2020;41(16):1588–99.
Carotid Baroreceptor Amplification
https://t.me/medicina_free
forTreatment ofResistant Hypertension
WilkoSpiering
20
Introduction
According to the recent American and European guidelines
for the management of arterial hypertension, resistant hypertension (RH) is dened as blood pressure (BP) that still
exceeds the target despite the use of three antihypertensive
medications in maximally tolerated daily doses with complementary mechanisms of action (a diuretic should be one
component) [1–3]. RH is an important cardiovascular risk
factor and is estimated to be present in 12–15% of hypertensive patients [3, 4]. Part of this population has so-called
pseudo-resistant hypertension due to white-coat hypertension, improper BP measurement and/or medication nonadherence [3]. After having excluded causes of
pseudo-resistant hypertension the true prevalence of resistant
hypertension is likely to be ~10% of treated patients [4]. This
true RH population might benet from non-pharmacological
device-based treatments.
Four major pathways contributing to the pathogenesis of
resistant hypertension are sodium overload, arterial stiffness,
endothelial dysfunction and high sympathetic activity [5].
Most of the available device-based treatments have been
designed to reduce the sympathetic nervous system outow.
Two device-based treatments target the sympathetic nervous
system specically at the level of the carotid sinus: baroreex activation therapy (BAT) and endovascular baroreex
amplication (EVBA). Both treatments try to amplify the
baroreex, that plays a central role in BP regulation. In
recent years, these treatments have been increasingly studied
in patients with RH.
Carotid Baroreceptors andResistant
Hypertension
Baroreceptors consist of stretch-sensitive bers and are
located in the area of the aortic arch and both carotid sinuses
near the carotid bifurcation. Baroreceptors provide the afferent signals in a negative-feedback circuit in the medulla that
maintains blood pressure at normal levels. The receptors
become active when the vessel wall stretches due to pulse
waves by an increase in blood pressure [6]. Subsequently, the
signal is passed via the glossopharyngeal nerve to the nucleus
tractus solitarius (NTS) in the dorsal medulla located in the
brainstem. The primary afferent axons in the NTS synapse
onto second-order neurons which in turn send excitatory projections to the GABAergic neurons in the region of the caudal ventrolateral medulla (CVLM). Then, the CVLM neurons
synapse directly onto the excitatory rostral ventrolateral
medulla (RVLM) neurons and inhibit the spontaneous activity of the RVLM [7]. As a consequence, the sympathetic tone
is reduced and the parasympathetic tone is increased, nally
leading to vasodilatation with consecutive normalization of
the BP.
In hypertension, it is hypothesized that the baroreceptor
sensitivity is reset to a higher operating pressure. Possible
explanations for this phenomenon are direct damage to the
receptors, a change in the coupling between the receptors
and the vascular walls, genetically determined properties of
the receptors, and decreased distensibility of the vascular
walls in which the receptors are embedded [6].
W. Spiering (*)
Department of Vascular Medicine, University Medical Center
Utrecht, Utrecht University, Utrecht, the Netherlands
e-mail: W.Spiering@umcutrecht.nl
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_20
Baroreex Activation Therapy (BAT)
Early studies in the 1960s, using devices to electrically stimulate the carotid sinus nerve, showed favorable results
regarding BP reduction [8–10]. However, baroreex stimulation through electrodes wrapped around the carotid sinus
nerve was halted due to technical difculties with electrode
implantation, adverse effects related to nerve injury and the
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introduction of more effective and better tolerated antihypertensive drugs [11]. This remained unchanged until 2001
when CVRx (Minneapolis, MN, USA), introduced an
improved carotid baroreceptor pacemaker addressing previous limitations: the rst-generation electrical carotid sinus
stimulator, the Rheos device (Fig.20.1a) [12].
a
Rheos Device
The Rheos device consisted of two pulse generators that
were surgically implanted around the carotid bulbs bilaterally along with a pulse generator placed in a subcutaneous
pocket in the chest. Preclinical studies in dogs showed that
b
c
Fig. 20.1 Devices for baroreex amplication. (a) The Rheos device
(rst generation) consists of bilateral electrodes and an implantable
pulse generator. The bipolar electrodes in tripolar conguration are
placed around both carotid sinuses and will electrically activate the
baroreceptors. (b) The Barostim neo device (second generation) consists of a unilateral electrode and lead and an implantable pulse genera-
d
tor. The electrode is sutured onto the arterial wall and will stimulate the
carotid sinus. (c) The MobiusHD is delivered by a catheter which is
introduced over a guidewire via the femoral artery. (d) The selfexpanding nitinol MobiusHD device which is implanted in the internal
carotid artery for amplication of the carotid baroreceptor signal
20 Carotid Baroreceptor Amplication forTreatment ofResistant Hypertension
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7days continuous baroreex activation therapy (BAT) by the
Rheos device resulted in a substantial and sustained reduction in mean arterial pressure, heart rate and norepinephrine
levels, without a compensatory increase in plasma renin
activity [13].
The open-label, non-randomized Rheos Feasibility Trial
(ClinicalTrials.gov: NCT01077180) studied the response of
ten patients with RH to baroreex activation therapy using
the Rheos system [14]. This study showed a mean reduction
in ofce systolic BP of 41mm Hg (range 22–104mm Hg;
p<0.001) with a peak response at 4.8V (p<0.001) without
signicant bradycardia or bothersome symptoms [14].
Subsequently, the multicenter non-randomized feasibility
Device-Based Therapy in Hypertension (DEBuT-HT,
ClinicalTrials.gov: NCT00710190) study assessed BP reduction and safety at 3-months post implantation in 45 patients
with a BP of ≥160/90 mm Hg while on treatment with at
least two antihypertensive drugs [15]. The study demonstrated a decrease in mean ofce BP of 21±4/12±2mm Hg
after 3months and 33±8/22±6mm Hg after 2years [15].
Despite these encouraging results, data regarding the durability of the antihypertensive action obtained in a randomized trial was lacking.
To overcome this limitation, the double-blind randomized
Rheos Pivotal trial (ClinicalTrials.gov: NCT00442286) was
designed [16]. The Rheos Pivotal trial assessed the safety
and efcacy of BAT in 265 patients with RH. One month
after implantation of the Rheos device each patient was randomly assigned to either immediate initiation of baroreceptor stimulation (group A, n=181) or delayed initiation until
the 6-month follow-up (group B, n= 84). In this trial, ve
co-primary endpoints were pre-specied: (1) acute responder
rate at 6months, (2) sustained responder rate at 12months,
(3) procedure safety, (4) BAT safety, and (5) device safety.
The acute efcacy endpoint (proportion of subjects that
achieve at least a 10mm Hg drop in systolic BP at month 6
compared with baseline, with a superiority margin of 20%)
was reached in 54% of the subjects in group A and 46% of
the subjects in group B, which was not statistically signicant. Moreover, the criteria for procedural safety were not
met as 25.5% of the patients suffered from surgical complications, wound complications or nerve injury [16]. However,
the mean reduction in systolic BP after 6months compared
to baseline was 16±29mm Hg in the stimulated group versus 9±29mm Hg in the control group (p=0.08) and longterm follow-up of 22 to 53months of the Rheos Pivotal trial
alone showed sustained reduction of mean systolic BP of
35± 31mm Hg versus pre-implantation among responders
[17]. A combined long-term follow-up study of the Rheos
Feasibility Trial, the DEBuT-HT Trial and the Rheos Pivotal
Trial showed sustained effect on BP after 6years of follow up (mean ofce BP 179±24/103±16mm Hg before treatment and 144 ± 28/85 ± 18 mm Hg after treatment) [18].
Major drawbacks for use of the rst-generation Rheos device
in standard clinical practice were its invasiveness and short
battery life which needs replacement every 3–5years. Based
on these mixed results, a considerable number of surgical
complications and nerve injury the US Food and Drug
Administration (FDA) did not approve the Rheos system for
the treatment of RH. Therefore, the Rheos system is not
available anymore.
Barostim Neo Device
The second-generation device (Barostim neo) (Fig.20.1b),
which is approved and clinically applied in Europe, uses a
smaller, one-sided unipolar disk electrode to decrease invasiveness and to improve battery life. The uncontrolled, openlabel Neo Non-Randomized Hypertension Study
(ClinicalTrials.gov: NCT01471834) was the rst study
investigating the efcacy of the device [19]. This trial
included 30 patients with RH from seven centers in Europe
and Canada and showed a mean reduction in ofce systolic
and diastolic BP of 26±4 and 12±3mm Hg, respectively,
at 6 months. Interestingly, a subset of six individuals who
already underwent renal denervation demonstrated similar
reductions in BP after implantation of the Barostim neo
implying that baroreex activation works through mechanisms broader than inhibition of renal sympathetic nerve
activity. Moreover, within the rst 30days after implantation
of the Barostim neo 90% of patients were free from systemor procedure-related events, compared with 75% in the
Rheos Pivotal Trial and the few events that did occur resolved
without sequelae. A few years later, the device was further
studied in a single-arm study among 51 patients with
RH.This study reported a signicant decrease in mean 24-hr
ambulatory systolic BP (from 148±17 to 140±23mm Hg;
p<0.01) and diastolic BP (from 82±13 to 77±15mm Hg;
p<0.01) at 6months after the procedure [20].
Another study that investigated the sympathetic vasoconstrictor tone and BP response of the Barostim neo device in
18 patients with RH reported that stimulation with intensities
that produced tolerable adverse effects in the short term
resulted in a mean decrease in ofce systolic BP of
17 ± 15 mm Hg (p = 0.002) [21]. However, 12 of these
patients (66.7%) experienced stimulation-related side effects
such as jaw or neck pain, globus or swallowing sensation,
coughing, or voice problems. In these patients, stimulation
intensity for the long-term treatment therefore had to be
reduced. This reduced stimulation intensity resulted in a signicant reduction in efcacy with a mean decrease in ofce
systolic BP of only 6±7mm Hg (p=0.028) [21].
Long-term follow-up of patients treated in the Neo NonRandomized Hypertension Study showed a sustained
BP-lowering effect (mean ofce systolic BP reduction of
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W. Spiering
26± 35mm Hg) of unilateral BAT and an acute effect of
device deactivation and reactivation on BP after 16.5months
of BAT, supporting the efcacy of BAT [22]. The largest
reported cohort treated with the Barostim neo so far demonstrated long-term BP reduction in 60 patients with RH [23].
Patients were dened as responders if they showed a reduction in systolic BP of ≥10mm Hg in ofce and/or≥5mm
Hg in ambulatory BP monitoring (ABPM). Twenty-four
months after implantation of the Barostim neo, 35 patients
(70%) could be classied as a responder according to ofce
measurements and 21 patients (46%) could be classied as a
responder according to the ABPM criterion. Overall, 50% of
the patients reached target ofce systolic BP of 140mm Hg
or below [23].
Finally, BAT also seems to be effective for lowering BP in
RH patients with renal failure. Wallbach et al. studied 23
chronic kidney disease patients with RH treated with the
Barostim neo. They found a mean ofce BP fall of 17/9mm
Hg as compared to 1/1mm Hg fall in 21 patients in the control group (standard medical management) after 6 months
(p<0.01) [24]. Beige etal. investigated the effect of BAT
with the Barostim neo in seven patients with end-stage renal
disease and RH [25]. They found a signicant decrease in
ofce systolic BP from 194 ± 28 to 137 ± 16 mm Hg
(p<0.01).
Ongoing Research inBAT
Studies to date have shown promising results with the
Barostim neo device. However, randomized sham-controlled
trials are needed to conrm the effects of the Barostim neo
on both ofce and 24-hr ABPM.Also, it is important to learn
the cost-effectiveness of this therapy compared with usual
care in patients with RH as this therapy is expensive and
requires battery replacements over time.
Two randomized studies are currently in progress that
will study BAT with the Barostim neo: the Economic
Evaluation of Baroreceptor STIMulation for the Treatment
of Resistant HyperTensioN (ESTIM-rHTN) study and the
Nordic BAT study. The ESTIM-rHTN study (ClinicalTrials.
gov: NCT02364310) is a randomized open-label trial which
aims to enroll 128 patients to compare the ambulatory daytime systolic BP of BAT with usual care in patients with RH,
also to compute the incremental cost-effective ratio (to identify the extra cost of BAT in BP reduction compared to usual
care) and the trial is expected to be completed in 2022. The
Nordic BAT study (ClinicalTrials.gov: NCT02572024) is a
randomized double-blind trial which aims to enroll 100
patients to compare the 24-hr ambulatory systolic BP of BAT
with usual care in patients with RH and the trial is expected
to be completed in 2028.
BAT inHeart Failure
BAT with the Barostim neo was also studied in patients
with heart failure and reduced ejection fraction (HFrEF), as
there is an increased activity of the sympathetic nervous
system in these patients. The BeAT-HF (Baroreex
Activation Therapy for Heart Failure, ClinicalTrials.gov:
NCT02627196) trial was a multicenter, prospective, randomized, controlled trial in patients with HFrEF [26].
Subjects were randomized 1:1 to receive either BAT plus
optimal medical management (BAT group) or optimal medical management alone (control group). Effectiveness endpoints were the change from baseline to 6months in 6-min
hall walk distance (6MHW), Minnesota Living with HF
Questionnaire quality-of-life (QOL) score, and N-terminal
pro-B-type natriuretic peptide (NT-proBNP) levels. The
safety endpoint included the major adverse neurological or
cardiovascular system or procedure- related event rate
(MANCE). The study showed that the Barostim neo signicantly improved quality of life score (14 points more than
the control group (Δ=−14 [95% CI: −19 to −9 points]),
exercise capacity (60m greater increase in 6MHW in BAT
versus control (Δ=60 [95% CI: 40–80m]), and NT-proBNP
(25% greater reduction in NT-proBNP compared to the
control group (Δ = −25% [95% CI: −38 to −9%]). BAT
showed to be safe, as the MANCE free rate was 97% (95%
CI: 93–100%) [26].
Endovascular Baroreex Amplication
(EVBA)
An alternative approach to amplify the baroreceptors in RH
is to use an endovascular implant to increase circumferential
and longitudinal wall strain at the level of the carotid baroreceptors, potentially resulting in amplication of the baroreex and lowering of BP.
Observations from years of research on carotid baroreceptors led to exploration of alternative baroreceptor reex
activity enhancement by increasing carotid bulb stretch during the systolic phase of the cardiac cycle. One would expect
increased strain in the carotid bulb with increasing bulb
radius, decreasing wall thickness, and/or increasing pressure. It not possible to non-surgically decrease the carotid
bulb wall thickness or to increase the blood pressure to
achieve an increased baroreceptor response. However, an
endovascular device has been developed that can increase
the strain at the level of the carotid sinus: the MobiusHD
device.
MobiusHD Device
The MobiusHD (Vascular Dynamics, Mountain View, CA,
USA) is a nitinol self-expanding rectangular cuboid implant
that was developed as a non-surgical alternative for increas-
20 Carotid Baroreceptor Amplication forTreatment ofResistant Hypertension
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203
ing stretch by reshaping the artery to a non-circular crosssection to increase carotid sinus wall strain without impacting
pulsatility and pressure. To better understand the stress–
strain relationships and evaluate potential carotid ow
changes, a uid structure interaction simulation analysis
with contact surface between the device and the arterial wall
was conducted [27]. Results indicated that device deployment in the carotid sinus induces an increase of 2.5% and
7.5% in circumferential and longitudinal wall stretch, respectively, and this led to a maximum of 54% increase in von
Mises arterial stress at the carotid sinus wall baroreceptor
region. In addition, device implantation had minimal effect
on blood-ow patterns. Based upon these uid–structure
interaction simulations, the MobiusHD induces localized
increases in wall stretch at the sinus, suggesting that this will
activate baroreceptors, with no consequential deleterious
effects on carotid sinus hemodynamics. The next step was to
study the device in a preclinical model. Unfortunately, very
few animals have a carotid sinus and/or baroreceptors and
this created challenges in developing an animal surrogate
model to predict human outcomes.
In an acute study in dogs, the MobiusHD induced a more
pronounced increase in carotid sinus nerve activity than a
standard carotid stent. Blood pressure was reduced by around
50/30mm Hg, which was sustained for 6h after implantation
without resetting or extinguishing of the hemodynamic
effects [28]. Long-term efcacy, however, was not possible
because the canine carotid sinus is typically less than 1mm
in diameter, which leads to difculty in maintaining device
patency for extended periods of time.
The CALM-FIM (Controlling And Lowering BP with the
MobiusHD– First In Man) study was the rst one to study
the safety and efcacy of the Mobius HD in humans. This
study is a prospective multicenter single-arm safety study
among European (CALM-FIM_EUR, ClinicalTrials.gov:
NCT01911897) and US (CALM-FIM_US, ClinicalTrials.
gov: NCT01831895) adult patients with resistant hypertension. The CALM-FIM studies were prospective, nonrandomized, rst-in-human studies that enrolled patients with
resistant hypertension (ofce systolic BP ≥160mm Hg and
mean 24-h ambulatory BP ≥130/80mm Hg despite a stable
regimen of ≥3 antihypertensive medications, including a
diuretic agent). The primary endpoint was the incidence of
serious adverse events at 6 months. Secondary endpoints
included changes in ofce and 24-h ambulatory BP.The rst
results of the CALM-FIM_EUR study in the 30 European
patients on the 6months of follow-up showed serious adverse
events in four patients (13%) and the reductions in mean
ofce and 24-hr ambulatory BP at 6months were 24/12mm
Hg (95% CI: 13–34/6–18mm Hg) and 21/12mm Hg (95%
CI:14–29/7–16 mm Hg), respectively [28]. Recently, the
nal long-term (3-year) safety and effectiveness of the
MobiusHD from the combined European and US CALM-
FIM cohorts were reported [29]. The MobiusHD was
implanted in 47 patients (30 in Europe, 17 in the United
States; mean age 54years, 23 women). Five serious adverse
events occurred within 30days postprocedure, all of which
were related to the device or procedure: two patients experienced severe hypotension requiring (prolonged) hospitalization for intravenous treatment and reduction of
antihypertensive medication; one patient had a hypertensive
crisis requiring hospitalization; one patient developed symptoms of acute lower extremity ischemia due to a dislodged
femoral closure device, which was treated surgically; and
one patient had a large groin hematoma causing hypotension
that required volume resuscitation. In addition, two TIAs
with neurologic ndings corresponding to the ipsilateral vascular territory of the implant (but without conrmed stroke)
occurred and were also attributed to the device or procedure.
Six serious adverse or cerebrovascular events occurred more
than 30days postprocedure. Two patients had strokes at 24
and 31months after implantation, the rst on the contralateral side of the implant, the second ipsilateral. One patient
experienced transient neurologic symptoms from the ipsilateral vascular territory of the device 30 months after
MobiusHD implantation. Findings on diffusion-weighted
magnetic resonance imaging were normal. Cerebral angiography showed a distal internal carotid artery stenosis, which
was present before MobiusHD implantation. One patient
required hospitalization for hypertension 3 months after
treatment, and two patients experienced severe hypotension
with syncope at 11and 32months post implantation. Ofce
BP decreased from baseline by 25/12 mm Hg (95% CI:
17–33/8–17mm Hg) at 6months, 24/12mm Hg (95% CI:
16–32/8–17 mm Hg) at 1 year, 19/11 mm Hg (95% CI:
11–27/6–15mm Hg) at 2years, and 30/12mm Hg (95% CI:
21–38/8–17mm Hg) at 3years. Mean 24-hour ambulatory
BP decreased by 20/11mm Hg (95% CI: 14–25/8–15mm
Hg) at 6months. The BP reductions occurred despite a trend
toward reduction in antihypertensive medication during follow- up. Interestingly, heart rate did not change from baseline
to 3years. It was concluded that EVBA with the MobiusHD
was effective in reducing BP at 3-year follow-up and appears
to have an acceptable safety prole in patients with uncomplicated implantation, although data from randomized shamcontrolled trials are needed to further evaluate the risk-benet
prole.
In a proof-of-principle single-center sub-study of the
CALM-DIEM study (Controlling And Lowering blood pressure with the MobiusHD-DefIning Efcacy Markers,
ClinicalTrials.gov: NCT02827032) the effects of EVBA on
muscle sympathetic nerve activity (MSNA) and baroreceptor
sensitivity were being studied, at baseline and 3months after
MobiusHD implantation [30]. In total 14 patients with resistant hypertension were treated with EVBA, of whom in ten
patients the MSNA data could be used for evaluation. MSNA
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burst frequency and burst incidence decreased in 6 of 10
patients: mean change −4.1 bursts/min (95% CI –12.2 to
4.0) and−3.8 bursts/100 heartbeats (−15.2 to 7.7). Change
in MSNA and BP were not correlated. In contrast, baroreex
sensitivity and cardiovascular responses remained unchanged
after EVBA.
Ongoing Research inEVBA
Despite these promising results randomized, double-blind,
sham-controlled clinical trials are needed to conrm the
safety and efcacy of EVBA with the MobiusHD device.
Therefore, two randomized, double-blind, sham-controlled
studies were initiated, CALM-START (ClinicalTrials.gov:
NCT02804087) and CALM-2 (ClinicalTrials.gov:
NCT03179800). The CALM-START study aimed to eliminate the confounding effects of antihypertensive medications
on the efcacy of the MobiusHD device, so after washout of
such medications. The sponsor of the trial decided to terminate the study due to the rigorous nature of the trial and
enrollment interruptions caused by COVID-19. The study
enrolled only four of the planned 110 subjects. The pivotal
CALM-2 study aimed to enroll 300 patients with RH, meaning mean 24-h ambulatory systolic BP ≥145mm Hg with a
minimum required dosing regimen of an angiotensinconverting enzyme inhibitor or angiotensin receptor blocker,
a calcium channel blocker, and a diuretic. The primary effectiveness endpoint is change in mean 24-h ambulatory systolic BP from baseline to the 180-day visit. Non-adherence
to antihypertensive medication is an important exclusion criterion. Although the design of the study is state of the art, the
inclusion criteria are rigorous and the study team therefore
was faced with poor enrollment, and therefore the sponsor
has decided to suspend the study and now has moved its
focus to heart failure. Currently, a proof-of-concept, openlabel study (HF-FIM, ClinicalTrials.gov: NCT04590001) is
initiated to evaluate the safety and effectiveness of the EVBA
with the MobiusHD in 40 patients with heart failure and
reduced ejection fraction. So, although the rst results of
EVBA in patients with RH are very promising the next necessary steps to prove the efcacy and take away concerns on
its safety seem to be delayed and it is unclear now whether
this treatment ever becomes available for patients with RH.
Conclusions
In recent years, more attention is being directed to identication of true RH and thereby identication of patients who
might benet most from device-based treatments. Since
sympathetic overactivity plays a crucial role in these patients,
device-based treatments targeting the sympathetic nervous
system at the level of the baroreceptors in the carotid sinus,
such as BAT and EVBA, are actively being studied.
Baroreex amplication either via the Barostim neo system
or by the endovascular MobiusHD device placement holds
promise as novel therapies to supplement, but not substitute,
pharmacological treatment for patients with true
RH.However, before implementation in clinical practice the
current evidence must be conrmed by results from ongoing
randomized, sham-controlled trials. Furthermore, future
research should also address to what extent the BP reduction
by these treatments reduce cardiovascular events and
mortality.
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Part VI
https://t.me/medicina_free
Unresolved Topics
Patient Selection forRenal Denervation
https://t.me/medicina_free
JulienDoublet, RomainBoulestreau, JulieGaudissard,
PhilippeGosse, andAntoineCremer
21
Following the initial controversial results of the Symplicity 3
trial in resistant hypertension (HTN) and thanks to the implementation of clinical studies with a particularly robust protocol, renal denervation has now been demonstrated to be
effective in improving blood pressure control. However, it
should be recognized that populations studied in pivotal trials have more or less similar clinical characteristics regarding age (mean age 55years) and co-morbidities (Table21.1)
and that the sample sizes remain small. Furthermore, it has
become clear that some patients do not respond to renal
denervation with a meaningful blood pressure reduction.
Hence, there are still many unanswered questions about
patient selection for denervation. This chapter summarizes
the current state of knowledge on response rates after renal
denervation, potential predictors and patient selection for
renal denervation.
The effectiveness of renal denervation is based on the
paradigm of a high sympathetic activity in individuals with
hypertension. The clinical relevance of this paradigm is supported by the blood pressure (BP) lowering effects of thoracolumbar sympathectomy in the rst half of the twentieth
century [1] and the known antihypertensive effects of some
central or peripheral inhibitors of sympathetic tone. Although
the role of sympathetic overactivity in raising BP is well
established, this does not necessarily mean that renal denervation is effective in a given hypertensive patient. In fact,
there is a signicant proportion of patients in whom the BP
cannot be reduced by denervation, so-called non-responders.
To optimize this promising technique, it is important to identify responders, because the procedure is invasive and
expensive.
Responder Rates inthePublished Literature
In SYMPLICITY 3, 58.3% of the 364 patients in the renal
denervation group experienced a>10 mmHg reduction in
systolic BP at 6months [2, 3]. The responder rate was higher
in the renal denervation group compared to the control group.
In the context of resistant HTN and with the 24-hour
ambulatory measurement (ABPM) as reference, the
DENER HTN study demonstrated a 24-hour systolic BP
reduction >20mmHg in 41.7% of patients at 6months in
the renal denervation group versus 20.8% in the control
group [4].
In the PRAGUE-15 study, two different strategies were
compared in the context of resistant HTN (triple therapy
including a diuretic) [5]. Renal denervation in addition to
continuation of the existing triple therapy was compared
with intensication of pharmacological treatment with spironolactone (in addition to existing triple therapy in the control group). At 6months, based on ABPM, 24h systolic BP
decreased signicantly in the renal denervation group
(−8.6mmHg). The authors dened the response to denerva-
J. Doublet · R. Boulestreau · J. Gaudissard · P. Gosse
ESH Hypertension Excellence Centre, Service de cardiologie et
d’HTA, Hôpital Saint André, CHU de Bordeaux, Bordeaux, France
A. Cremer (*)
ESH Hypertension Excellence Centre, Service de cardiologie et
d’HTA, Hôpital Saint André, CHU de Bordeaux, Bordeaux, France
ESH Excellence Centre, Hypertension Unit, Hôpital Saint André,
CHU de Bordeaux, Bordeaux, France
Bordeaux Population Health Center, Unité INSERM 1219,
Bordeaux, France
e-mail: antoine.cremer@chu-bordeaux.fr
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_21
209
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