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a
Drug Composite I
=×
()
18 Sensing Renal Nerve Activity Before, During andAfter Denervation: SyMap
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Fig. 18.6 Renal Mapping
and Ablation System
developed by SyMap Medical
Ltd., consisted of SyMapCath
I™ catheter (a) and
SYMPIONEER S1™
Stimulator/Generator (b)
b
187
SMART Study andPreliminary Results
1. The control rates of ofce systolic blood pressure
(SBP<140mmHg)
The ongoing Sympathetic Mapping/Ablation of Renal
2. The composite index of antihypertensive drugs
Nerves Trial (SMART Study, ClinicalTrials.gov ID:
NCT02761811) aims to evaluate the safety and efcacy of
targeted renal sympathetic denervation using the system in
patients with pharmacotherapy and uncontrolled hypertension for at least 6months, and then after standardized antihypertensive drug therapy (at least two classes of drugs) for at
least 28days while ofce systolic BP is still ≥150 mmHg
and≤180mmHg.
There will be two primary endpoints: Magnitude of the
blood pressure reduction and drug burden of antihypertensive medications after renal ablation. Design of most current
clinical trials are focused on the former and ample data have
emerged for this question; the latter, however, has not been
sufciently addressed. We believe that changes of antihypertensive drugs should be a major clinical endpoint for RDN
trials. The views of Weber etal. support this view [28]. In a
clinical setting, the design using reduction in BP as the major
clinical endpoint faces an important challenge: convincing
patients not to alter their antihypertensive regimen even
when their BP is still ≧150mmHg after RDN, this pertains
particularly to patients in the sham group during six-month
follow-up. If patients in sham group take any antihypertensive drugs to manage their high BP, the difference of ofce
systolic BP between RDN and sham group could be compromised since the efcacy of global RDN is around 10mmHg
[6, 9, 10].
Thus, we included two primary endpoints at 6 months
after RDN for SMART study:
The Composite Index is derived from the numbers of antihypertensive drugs and doses of the medications as below:
ndex Weightssum of doses
Weights is the number of classes of antihypertensive drugs.
One standard dose is dened as 1, a half dose is dened as
0.5, and double dose is dened as 2.
For instance, if a patient takes one dose of an angiotensin
II receptor blocker and one dose of a calcium blocker, this
patient’s Drug Composite Index is: 2×(1+1)=4.
Via this trial, we will be able to tell patients and physi-
cians how many antihypertensive drugs are taken less after
RDN.
During the RDN procedure, renal mapping and selective
denervation are performed. Renal nerve stimulation is delivered for 60seconds at 15mA, 20Hz and pulse duration of
5ms, and hot spots are ablated for 2min at 8–10watts and
50 °C. If an unsatised response to RDN is encountered
which can be identied by a post procedure stimulation continuing to cause a BP increase, a repeat RDN is performed at
the same site.
This is a prospective, multicenter, single blinded, ran-
domized and sham controlled trial, and patients will be
informed, given consent and are entered into a screening process. During the screening period, patients will receive a
standardized antihypertensive drug treatment for at least
28days and if ofce BP is still ≥150mmHg, and≤180mmHg
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Table 18.1 Standardized antihypertensive drug regimen: SMART Study
Commercial Name
Class Generic name
1 Angiotensin
Receptor
Blocker
2 Calcium
Channel
blocker
3
β-Receptor
blocker
4 Diuretic Hydrochlorothiazide
5
α-Receptor
blocker
6 Combination
drug
Irbesartan Tablets APROVEL ® (Sano) 150mg/day 300mg/day
Amlodipine Besylate
tablets
Metoprolol Succinate
Sustained-release
tablets
Tablets
Terazosin
Hydrochloride
Tablets
Irbesartan and
Hydrochlorothiazide
Tablets
Manufacturers Standard Dose Maximum Dose
NORVASC ® (Pzer) 5mg/day 10mg/day
BETALOC ZOK®
(AstraZeneca)
Hydrochlorothiazide tablets
(Changzhou pharmaceutical
factory co ltd., China)
HYTRIN ® (Abbott) 2mg/day 4mg/day
COAPROVEL ® (Sano) Irbesartan
47.5mg/day 95mg/day
25mg/day 50mg/day
150mg+hydrochlorothiazide
12.5mg/day
Irbesartan
300mg+hydrochlorothiazide
25mg/day
J. Wang et al.
Table 18.2 Numbers of hot spots, cold spots and neutral spots in
response to electrical renal stimulation in patients with uncontrolled
hypertension (n=10 Patients)
Renal mapping results
Left renal
artery
Total Stimulation Sites 82 75 157
Average Stimulations/
kidney
Total Hot Sites Identied
(% of total maps)
Average Hot Sites/kidney
(ablated)
2nd Ablation Required
(%)
8.2 7.5 15.7
41 (50%) 44 (59%) 85
4.1 4.4 8.5
16 (39%) 18 (41%) 34
Right renal
artery Total
(54%)
(40%)
and they meet the inclusion and exclusion criteria these
patients are included. Renal artery angiography will be performed and the patients are allocated to either renal sympathetic nerve denervation or renal artery angiography only in
a 1:1 randomized fashion (220 patients, 110 pairs). Patients
with ofce BP that haven’t achieved an ideal level
(<140mmHg) 3months after RDN will titrate doses and/or
classes of antihypertensive drugs according to a predened
standardized medication regimen until their ofce BP
<140 mmHg. All medications are provided by the study
sponsor (SyMap Medical (Suzhou), Ltd.) and titrated antihypertensive drugs must only be chosen from the standardized
drug regimen (Table18.1). The class/dose and order of drug
titration are rigorously dened. Physicians who perform
post-procedure patient management and physicians who perform RDN procedures are blinded to whether or not the
patient underwent denervation. Patients will be followed for
7days after the procedure or at discharge from hospital and
at 1 month, 2 months, 3 months, 4 months, 5 months,
6months, 9months and 12months after the procedure. Urine
samples will be collected at the end of each screening,
3months, 6months and 12months to monitor antihypertensive drug compliance.
Preliminary data from the SMART Study were presented
at CRT 2017 (Washington DC) [29] and TCT 2019 (San
Francisco, USA) [30], and conrmed some of the theoretical
groundwork and preliminary data laid out as above. In ten
patients with uncontrolled hypertension, only 54% of sites
were responsive to renal stimulation with BP elevation (hot
spots) (Table 18.2). Perhaps most importantly, stimulation
resulted in a BP drop in 16% of sites (systolic BP−16mmHg,
diastolic BP −4mmHg, and mean BP− 7mmHg in average)
(Table18.3) and no BP response to stimulation in 29% of
sites. Ablation of the hot spots prevented BP elevation with
repeat stimulation intra-procedurally, which conrmed an
effective RDN.Otherwise, a second ablation was performed
at the same site. Long-term outcomes in the full study cohort
are still pending. Similar attempts to develop a mapping system were also made by Rainbow/Pythagoras (Israel).
Preliminary results were recently presented by Mahfoud,
Tsious, and Damen at EuroPCR 2017 and conrmed a heterogeneous response to a renal nerve stimulation based on
locations of stimulations, with a tendency towards higher BP
elevation and higher levels of energy in more proximal renal
artery locations [23, 31]. The continued development of
appropriate tools to test the renal nerve contribution to elevated BP may improve technical success of RDN, and ultimately allow targeted RDN.
The promise of a targeted, selective sympathetic RDN
opens up a number of possibilities which could address the
18 Sensing Renal Nerve Activity Before, During andAfter Denervation: SyMap
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Table 18.3 Changes in blood pressure in response to electrical renal stimulation in patients with uncontrolled hypertension (mmHg, Mean±SE,
n=10 patients)
SBP
Baseline
Hot Spots 172.1±4.4 185.9±4.5 13.8±1.1 87.1±2.4 94.9±2.4 8.1±0.7 116.9±2.8 124.6±2.7 8.2±0.8
Cold Spots 167.6±6.7 151.5±6.4
Neutral Spots 166.6±4.1 166.8±4.1 0.1±0.3 88.2±2.7 87.8±2.7
SBP systolic blood pressure, DBP diastolic blood pressure, MAP mean arterial pressure
SBP
Response △SBP
−16.2±1.7
DBP
Baseline
92.2±3.7 88.0±4.1
DBP
Response △DBP
−4.2±0.9
−0.4±0.3
MAP
Baseline
118.1±4.6 109.7±4.5
114.8±2.8 114.3±2.9
MAP
Response △MAP
−6.8±1.5
−0.4±0.4
189
limitations previously experienced with the conventional
approach of unselective or global RDN.Dedicated clinical
studies will need to prove the safety and efcacy of the selective RDN approach on long term BP reduction.
Conict of Interest J. Wang is a co-founder of SyMap Medical
(Suzhou), Ltd., China.
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Part V
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New Device-Based Concept for the Diagnosis
and Treatment of Hypertension
Transcatheter Carotid Body
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Denervation: First-in-Man Results
andFuture Directions
MelvinD.Lobo
19
Abbreviations
BP Blood pressure
CB Carotid body
COPD Chronic obstructive pulmonary disease
DBP Diastolic blood pressure
ISH Isolated systolic hypertension
IVUS Intravascular ultrasound
SBP Systolic blood pressure
SHR Spontaneously hypertensive rat
Rationale
Carotid Body Structure andFunction
The carotid body (CB) functions as the principal peripheral
polymodal chemoreceptor in man [1]. In response to key
stimuli such as hypoxemia and hypercapnoea, and to a
lesser extent acidosis, hypoglycemia and hypoperfusion, it
causes an increase in respiratory minute ventilation and in
sympathetic nervous system activation to the vasculature
and heart [2]. The CB is approximately the size of a grain
of rice and resides at the bifurcation of both of the common
carotid arteries [3] (Fig.19.1). Its innervation comes both
from the carotid sinus nerve (a branch of the glossopharyngeal nerve, which also supplies the carotid baroreceptors),
the vagus, and in addition it receives innervation from the
cervical sympathetic ganglion. Notably the CB has the
highest blood ow relative to tissue mass of any organ in
the body (2000mL/min per 100mg of tissue). Hypertrophy
M. D. Lobo (*)
Barts BP Centre of Excellence, Barts Heart Centre, St
Bartholomew’s Hospital, West Smitheld, London, UK
Barts NIHR Cardiovascular Biomedical Research Centre,
Charterhouse Square, William Harvey Research Institute, Queen
Mary University London, London, UK
e-mail: m.d.lobo@qmul.ac.uk
of the CB has been observed in the spontaneously hypertensive (SH) rat and in humans with hypertension when
compared to adult controls [4].
Stimulation of the CB increases blood pressure (BP)
through sympathetically mediated pathways involving the
nucleus tractus solitarius and the rostral ventrolateral
medulla resulting in increased renal sodium retention,
enhanced renin release and also vasoconstriction [5].
Importantly, whilst the chemoreex has a sympatho-excitatory effect, it acts concomitantly to suppress the baroreex
and thus both chemoreex and baroreex are inextricably
linked in the control of sympathetic tone [6]. It is believed
that chronic hyperactivity of the CB is a maladaptive
response which underlies diseases characterised by
increased sympathetic drive (e.g. hypertension, heart failure, obstructive sleep apnoea) and may thus be a potentially
important target for novel treatment approaches [7, 8].
Preclinical Data
Abundant evidence from animal models points toward a critical role of the CB in neurogenically mediated hypertension.
In a rat model of intermittent hypoxia, animals which underwent bilateral sectioning of the carotid sinus nerve did not
develop hypertension in response to hypoxic stimuli [9].
Furthermore, the development of hypertension following
hypoxia was also abrogated by treatment with 6-hydroxy
dopamine which selectively blocks peripheral sympathetic
neurones and demonstrates the sympatho-excitatory role of
the CB.
Subsequently, in developing and adult spontaneously
hypertensive rats (SHR), Abdala and colleagues demonstrated signicant BP reduction following bilateral carotid
sinus nerve sectioning but not in healthy normal animals
[10]. A concomitant improvement in baroreceptor function
was noted possibly due to resetting of central baroreceptor
control. The same group went on to show that transient
hyperoxia with 100% oxygen led to inactivation of the CB
© 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_19
193
194
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a b
M. D. Lobo
Internal
jugular vein
Carotid
bifurcation
Common
carotid artery
Fig. 19.1 The anatomy of the carotid body. (a) Schematic showing
location of the carotid bifurcation. (b) Gross anatomical appearance of
the human carotid body located at the carotid bifurcation. Legend: CB
Hyoid bone
and BP reduction in SHR and that this effect was absent
following carotid sinus nerve denervation suggesting that
tonic activity of the CB is critical for the hypertensive
response [11]. In this particular model, bilateral carotid
sinus nerve sectioning was required to produce BP reduction with no effect noted with unilateral resection (neither
right nor left). Furthermore it was demonstrated that renal
nerves were not necessary for the BP lowering effect of
carotid sinus denervation and that renal denervation and
carotid denervation had additive effects on BP reduction
regardless of which was carried out rst although carotid
denervation appeared to result in a larger BP reduction than
renal denervation alone [11].
From a safety perspective, bilateral carotid sinus nerve
transection in normotensive Sprague Dawley rats caused
only temporary reduction in the hypoxic ventilatory response
which returned after days to baseline values [12]. Moreover,
in hypertensive rats, bilateral carotid sinus nerve sectioning
resulted in transient reduction in respiratory rate which
recovered within 1week [10]. Taken together, these observations suggest functional reorganisation of the central oxygen
dependent chemoreex pathways, which has been observed
in other species following CB denervation and may in part be
due to redundancy of CB chemoceptors [13, 14].
CB
EC
IC
CC
carotid body, CC common carotid artery, EC external carotid artery, IC
internal carotid artery
Preliminary Clinical Data
CB Resection in15,000 Humans forChronic
Respiratory Disorders
Originally unilateral or bilateral CB resection was proposed
as a treatment for chronic lung diseases (e.g. asthma, chronic
obstructive pulmonary disease and emphysema) or undertaken in cases of CB tumours or carotid sinus syndrome. A
rich literature attests to the relative safety of the procedure
with only a single death from 15,000 reported cases directly
attributable to the procedure [8]. Not surprisingly there were
some procedural complications noted in these studies, most
notably a 3% incidence of transient hypoglossal paresis from
5600 reported cases and a<0.5% incidence of other adverse
effects such as headache, BP disorders or cerebrovascular
injury resulting in transient/permanent hemiparesis [8].
More recent data conrms the impairment of hypoxic ventilatory responses following bilateral carotid sinus nerve
denervation or bilateral CB excision which does not appear
to recover in humans compared to other species [15].
However, additional studies are called for and in particular
there is a need to address the effects of unilateral and bilateral CB removal in individuals without underlying lung
disease.
CHANGES IN BLOOD PRESSURE FOLLOWING
DATS DATS DATSVKS. VKS. VKS.NOS. NOS. NOS.
19 Transcatheter Carotid Body Denervation: First-in-Man Results andFuture Directions
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Fig. 19.2 Blood pressure
changes in asthmatic patients
after bilateral carotid body
(CB) resection. Arrows
indicate time of CB resection
with post-operative follow-up
until 6months. Note the
sustained BP reduction in the
hypertensive group [16]
MMHG
160
140
HYPERTENSIVE
GROUP
(29 CASES)
NORMAL GROUP
(598 CASES)
195
CAROTID BODY REMOVAL
HYPOTENSIVE GROUP
(21 CASES)
In patients who underwent CB excision for asthma in
Japan between the 1940s–1960s, Nakayama reported that
there were no effects on BP levels in normotensive individuals but that in 29 hypertensive patients, an immediate postoperative BP reduction of 40 mmHg from a baseline of
170mmHg was observed immediately after surgery and that
this reduction was sustained out to 6months of follow up
[16] (Fig.19.2). Similarly, Winter and Whipp noted immediate post-operative reduction of 20 mmHg in systolic BP
(SBP) in 32 patients who underwent bilateral CB resection
surgery for severe COPD [17].
Hyperoxia Studies
As noted with the experiments in rodents, studies in man also
indicate that the chemoreex can have an important role in
neurogenic hypertension. In young patients with diastolic
phase hypertension increased ventilatory and BP responses to
hypoxia were noted compared to healthy normotensive controls [18]. Furthermore in hypertensive males, respiration with
100% oxygen for 10min led to signicant reduction in muscle
sympathetic nerve activity and heart rate (compared to healthy
controls) although BP was unaffected [19]. Separately it was
shown that brief inactivation of the chemoreceptor achieved
through 3min respiration with 70% oxygen signicantly lowered SBP, diastolic BP (DBP) and total peripheral resistance in
mildly hypertensive young males [20]. In summary therefore
these studies support the notion that increased chemosensitivity resulting in augmented sympathetic drive may be a key
contributor to the early stages of human hypertension.
120
100
80
68
SYST. PR.
DIAST.PR.
PREOP. PREOP.
5726 57 26 5726
SYST. PR.
DIAST. PR. DIAST. PR.
PREOP.
SYST. PR.
First inMan Unilateral CB Resection Study
In 2016, the results of the rst prospective feasibility and
safety clinical trial on unilateral surgical CB removal for the
treatment of resistant hypertension were published [21]. In
this open label single arm study, patients with uncontrolled
hypertension despite taking on average 5.7 drugs, underwent
unilateral CB resection. The procedure was demonstrated to
be feasible and safe with no serious adverse events related to
the surgery. Overall there was no signicant change in either
ofce or ambulatory BP at any timepoint up until 12months
post-surgery. However, from a baseline blood pressure of
168/101±7/5mmHg, unilateral CB resection lowered SBP
by 26mm Hg in 57% of patients classed as responders who
evidenced >10mmHg drop in ambulatory BP at 3months of
follow up and also had histological evidence of glomus cells
in resected tissue.
In these eight responders a concomitant reduction in
muscle sympathetic nerve activity and improvement in
baroreflex sensitivity was also noted along with a reduction in requirement for antihypertensive medication.
Responders were noted to have higher peripheral chemoreflex sensitivity and drive and also consistently underwent resection of the right CB.These characteristics may
presumably inform future patient selection for CB modulation studies. The authors acknowledged the limitations
of the study and in particular the small sample size, lack
of control group and uncertainty regarding adherence to
medication which was not investigated at the time of
recruitment.
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M. D. Lobo
Procedure
Given that surgical CB resection is time consuming, requires
general anaesthesia and is non-scalable, less invasive
approaches to disrupt CB function are desirable. Recently
transcatheter CB ablation has become feasible using a dual
function diagnostic and ablation catheter coupled to a proprietary generator system (Cibiem®: Fig.19.3). This technology
enables localisation of the carotid body in the region of the
carotid bifurcation using intravascular ultrasound (IVUS)
imaging guidance. Using the same catheter, carotid body
ablation is achieved through the subsequent delivery of therapeutic ultrasound energy via the jugular vein. The procedure is carried out using conscious sedation and lasts
40–60min and utilises around 250ml of contrast medium.
a
b
Fig. 19.3 Endovascular carotid body ablation. The transcatheter
carotid body (CB) ablation procedure begins with identifying the origin
of carotid bifurcation using intravascular ultrasound (IVUS). Thereafter
the catheter is advanced to the desired height and ablation depth is measured using IVUS. Following this the use of an ultrasound-visible
marker to rotate and identify the space between the bifurcation permits
the operator to target the CB. (a) IVUS catheter in situ. (b) Proprietary
programmable power generator
Evidence
Transcatheter unilateral CB ablation has been evaluated in a
rst in man study with the dual objectives of establishing the
safety and efcacy of this novel system to ablate the right
carotid body and thereby improve BP control in patients with
resistant hypertension and to determine the durability of the
treatment effect. To date data from this study have only been
published in abstract form [22]. This was a single-arm, multicenter prospective study which included patients with
ofce BP ≥160/75 mmHg and daytime ambulatory SBP
>135mmHg despite a stable prescription of three or more
antihypertensive medications (including a diuretic) for at
least 6weeks prior to the procedure. CT angiography was
required to conrm the presence of the right CB.Exclusion
criteria were patients with signicant renal impairment
(eGFR < 30ml/min/1.73m2), obesity (BMI>40kg/m2) or
severe obstructive sleep apnoea (apnoea/hypopnoea index
>35/min) and those with prior interventional therapy for
hypertension.
The combined primary safety endpoint was composed of
rate of death, hospitalization for hypertensive crisis, and
device- or procedure-related serious adverse events (SAE) at
one-month post-treatment. The primary efcacy endpoint
was dened as the change in 24-h ambulatory SBP between
baseline and 1-, 3-, and 6-months post-treatment. Data from
this study was initially presented at the ESC 2017 Congress
(at which point long term follow up had been obtained in
only 10 patients) demonstrating a reduction in 24-h ambulatory SBP of 9±9/4±6mmHg at 1month post procedure and
of 10±15/4±7mmHg at 6months compared to baseline
ABPM.
During the ESC Congress 2018, further data from this
study was presented [23]. By this time a total of 39 patients
had been enrolled in the study with 6-months follow up data
being available from 29 patients. The study population had a
mean age of 63±11years and BMI of 30.2±4.3kg/m2, 69%
were male and 22% had diabetes. Despite the fact that
patients were prescribed an average of 4.6±1.9 antihypertensive medications, they exhibited uncontrolled hypertension with baseline ofce BP 170/93 ± 18/20 mmHg and
mean 24-h ambulatory BP of 154±13/94±13mmHg. It is
noteworthy that medicines adherence was not evaluated in
this study and furthermore that 44% of patients had isolated
a
19 Transcatheter Carotid Body Denervation: First-in-Man Results andFuture Directions
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197
b
Fig. 19.4 Ambulatory BP reduction following transcatheter carotid
body ablation. (a) Post-procedural reduction in 24h and daytime ambulatory BP. (b) Patients with isolated systolic hypertension demonstrate
a markedly attenuated response to CB ablation. Legend: ABPM ambu-
systolic hypertension at baseline (dened as ofce SBP
≥160mmHg and DBP <90mmHg).
All patients underwent IVUS-guided right carotid body
ablation. At 6months, other than a single TIA (probably
as a result of very high procedural BP), no major SAEs
had occurred suggesting that the procedure is safe and
that loss of unilateral CB function was not associated with
any medium term harm. Substantial reduction in 24-h
latory BP monitoring, ISH isolated systolic hypertension (dened as
ofce systolic BP ≥ 140 mmHg and diastolic BP < 90 mmHg at
baseline)
ambulatory SBP and DBP was noted from 1-month postprocedure and remained stable at 6 months conrming
sustained treatment effect (Fig.19.4a). Notably in patients
with isolated systolic hypertension there was a markedly
attenuated response to CB ablation (Fig. 19.4b) which
possibly attests to reduced contribution from elevated
sympathetic drive to maintenance of hypertension in this
patient group [24].
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