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17 Role of Aerent Nerves in High Blood Pressure and Approaching Renal Denervation Via the Collecting System: The Verve…
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abc
175
Fig. 17.3 Histopathology of the renal pelvic wall after renal pelvic
denervation. Renal pelvis (H&E Stain) with normal pelvis epithelium
(solid arrow), acute inammation of the mucosa and submucosa (open
Fig. 17.4 Image showing a direct visualization of an electrode ball
positioned in the renal pelvis and resultant blanching of the pelvic wall
after radiofrequency energy is applied to the electrode. The blanching
represents tissue heating after renal pelvic denervation
Other conditions associated with overactive sympathetic
drive including heart failure, type 2 diabetes mellitus, metabolic syndrome, obstructive sleep apnoea, and chronic kidney disease may procure benet from renal pelvic
denervation. This, however, merits further exploration.
Perspectives
Uncontrolled hypertension remains a challenging and growing clinical problem. Heart disease, stroke, and chronic kidney disease are largely preventable by controlling BP and
associated CV risk factors, among which dietary sodium
restriction is a potent, but neglected antihypertensive
approach. Nonadherence to chronic antihypertensive medicines is common and critically contributes to the associated
poor CV outcomes. The US survey of 1000 US residents
aged 30 and over reported that 30% of adults would rather
arrow) (a). Nerve injury with perineuronal brosis (open arrow), necrosis, and vacuolization (solid arrow) (b, c), with permission from [38]
risk shorter life than take daily medicine for CV prevention
[40]. Further arguments for the increased need for innovative
device-based antihypertensive therapy are drug intolerance,
middle-aged hypertensive patients, particularly women of
reproductive age, and a signicant number of adults with
uncontrolled hypertension for whom treatment goals should
be below 130/80mm Hg according to the ACC/AHA guideline and adults under the age of 65 as per ESH
recommendations.
Among potential candidates for arterial RDN, between
16–47% of patients have been reported not to be eligible for
bilateral RDN due to renal anatomy exclusion criteria [32,
41, 42] which is a major limiting factor. The predominance
of associated diseases (i.e. obesity, diabetes, chronic kidney
disease, smoking, aging) is common in patients with resistant hypertension, often related to isolated systolic hypertension in which the effectiveness of arterial RDN in lowering
BP is suboptimal [43, 44]. Nerve bers do not completely
converge on the renal artery until beyond the main bifurcation [45]. Arterial RDN primarily targets efferent nerves as
sympathetic nerves are in closer proximity to the arterial
lumen in more distal parts of the main artery [27]. In addition, currently, no marker exists to conrm arterial renal
nerve ablation or on-table BP reduction during the procedure. Given these obstacles, renal pelvic denervation provides an alternative and less invasive non-vascular approach
which can be performed under direct visualization using the
natural orice with no requirements for dye contrast and
arterial puncture, not dependent on the renal artery anatomy,
resulting in immediate on the table drop in BP and HR reduction in addition to neuromodulation. Currently, ongoing clinical trials will further dene the magnitude and durability of
BP reduction achieved with renal pelvic denervation in
human hypertension.
176
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D. Hering and R. R. Heuser
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Part IV
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Measurement of Renal Sympathetic Nerve Activity
and Guided Denervation
Sensing Renal Nerve Activity Before,
https://t.me/medicina_free
During andAfter Denervation: SyMap
JieWang, Yue-HuiYin, YueWang, WeiMa,
andWeijieChen
18
The Achilles Heel oftheField: Lack
ofFeedback toIndicate Ecient Renal
Sympathetic Denervation
The concept of RDN to treat hypertension can be traced back
to the 1950s. In a large scale study Smithwick and Thompson
showed that blood pressure (BP) and mortality of hypertensive patients were signicantly improved by thoracolumbar
splanchnicectomy [1], demonstrating the effectiveness of
RDN for the treatment of hypertension. Because of severe
side effects of surgical RDN and developments of pharmaceutical therapies, the surgical approach was ultimately
abandoned from clinical practice. Although sophisticated
drug therapies have been available for hypertension, new
therapies for the disease are still an unmet clinical need
mainly because of problems related to drug compliance as
well as drug resistance. There are 70 [2], 150 [3], and 245 [4]
million hypertensive patients in US, EU countries and China,
respectively, and the uncontrolled rate is very high. Krum
etal. for the rst time developed a percutaneous treatment
J. Wang (*)
Division of Cardiology, Department of Medicine, College of
Physicians & Surgeons, Columbia University, New York, NY, USA
Academy of Clinical and Translational Research, Jiangsu Province
Hospital, The First Afliated Hospital with Nanjing Medical
University, Nanjing, China
SyMap Medical (Suzhou), Ltd., Suzhou, China
e-mail: jw147@columbia.edu
Y.-H. Yin · W. Chen
Department of Cardiology, The Second Afliated Hospital of
Chongqing Medical University, Chongqing, China
Y. Wang
Academy of Clinical and Translational Research, Jiangsu Province
Hospital, The First Afliated Hospital with Nanjing Medical
University, Nanjing, China
SyMap Medical (Suzhou), Ltd., Suzhou, China
W. Ma
Department of Cardiology, Peking University First Hospital,
Beijing, China
option for essential arterial hypertension and, in 2009, published the rst proof-of-concept study demonstrating that
renal denervation using a dedicated catheter in patients with
resistant hypertension can lead to a signicant reduction in
BP with an excellent safety prole [5]. Since then, a series of
clinical studies have conrmed the efcacy and safety of
RDN to treat hypertension [6–10]. However, Symplicity
HTN-3 [11], the rst double-blinded, randomized, sham
controlled trial failed to demonstrate the expected blood
pressure reduction at 6 months. Some investigators suggested that two major factors may have interfered with the
effects of device-based RDN on BP and led to the failure of
the Symplicity HTN-3 study: poor drug compliance during
the trial, and lack of operator feedback during and after RDN
to conrm an effective renal sympathetic denervation coupled with operator inexperience and insufcient ablation
[12]. The more recent Spyral Global Off-Med and On-Med
studies using a second generation device addressing some of
the shortcomings of the rst generation single electrode
Symplicity catheter as well as drug compliance conrmed
the efcacy and safety of RDN but the average ofce systolic
BP reduction was moderate (~10mmHg) because 20–30%
patients were so-called non-responders whose BP did not
decrease or even increased after RDN [6, 9, 10]. The nonresponder or paradoxical responder (patients whose blood
pressure increased after renal denervation) rates may counteract average BP-lowering effects achieved by RDN. This
phenomenon was consistently observed across all energybased RDN devices evaluated so far. Per Townsend and
Sobotka [13], either radiofrequency ablation or ultrasound
ablation had an over-all success rate of about 63%. Of note,
an approximate 30% non-responder rate was also observed
among patients with alcohol-mediated RDN.Mahfoud etal.
reported that decreases of ≥5 and ≥10mm Hg in ofce systolic BP at 6 months were recorded in 70% and 61% of
patients, respectively [14]. Townsend and Sobotka believed
that the ~30% non-responder rates may reect either technical failures or suboptimal patient selection given the lack of
predictors for BP-lowering success. Renal denervation is a
© 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_18
181
182
ab
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J. Wang et al.
costly and invasive procedure and it is, therefore, obvious
that the signicant non-responder rate needs to be addressed.
As Esler pointed out, failure to test an effective renal sympathetic denervation “represents the Achilles heel of the eld”
[15]. Thus, indicators before, during and after the RDN
procedure to predict and conrm a successful sympathetic
denervation is desirable for this therapy.
Mapping Renal Nerves by Renal Nerve
Stimulation: Anatomical, Physiological
andHistological Evidence
Recent developments based on studies of anatomy, physiology and histology in this eld made mapping renal nerves
and selective RDN possible. Van Amsterdam et al. and
Mompeo etal. [16, 17] examined neural anatomical structures around the renal artery and revealed three nerve types:
sympathetic, parasympathetic and afferent nerve components (Fig.18.1); however, Kuichi etal. had different views
about the types of these nerves and named these nerves as
“pressor nerves”, “depressor nerves” and “neutral nerves”
depending upon whether BP was increased, decreased or
unchanged in responses to electrical stimulation [12]. We
[18–20] and other investigators [21, 22] have demonstrated
that systemic hemodynamics in particular, BP, was increased,
decreased or unchanged once an electronic stimulation was
delivered to the renal artery, respectively. The direction of
change in BP due to the stimulation depends upon which
type of renal nerves was activated. We [18] named the sites
which increased BP when stimulated as “hot spots”, representing sympathetic dominant innervations, the sites which
lowered BP when simulated as “cold spots”, representing
parasympathetic dominant innervations, and locations along
the renal artery which do not show hemodynamic effects
when stimulated as “neutral spots,” which may present no
innervations or well-balanced sympathetic and parasympathetic innervations (Fig.18.2). Mapping sympathetic/pressor
nerves or hot spots for selective ablations and limiting denervation to these areas could be expected to cause a signicant
fall in BP whereas ablations of parasympathetic/depressor
nerves or cold spots may result in no effects or even an
increase in BP [18, 23]; neither of the latter spots should be
ablated [12]. Results from clinical trials did show increased
BP in some patients after RDN at a 6-month follow-up [6, 9,
10]. It is conceivable that this effect may have been due to
predominant ablation of cold spots. As Tsious et al. [23]
pointed out, renal nerve bers vary signicantly regarding
a
a
Fig. 18.1 Panel A shows the renal sympathetic renal plexus of a
human right kidney. (a) Anterior view and (b) posterior view. Ag (adrenal gland), Arg (aorticorenal ganglion), Coe (coeliac ganglion), CoT
(coeliac trunk), Ig (renal inferior ganglion), LC (contribution of the
lumbar chain to the renal plexus), Pg (renal posterior ganglion), RK
(right kidney), SMg (superior mesenteric ganglion), SP (thoracic
splanchnic nerves). Panel B shows stained slides of the same artery and
b
c
segment for immuno-histological markers. The upper left corner is the
lumen of the artery. (a) TH, marker for sympathetic, (b) NOS, marker
for parasympathetic, (c) CGRP, marker for afferent, (d) PGP, marker for
general marker. TH (tyrosine hydroxylase), NOS (nitric oxide synthase), CGRP (calcitonin gene related peptide), PGP (Protein Gene
Product 9.5). Adapted with permission from van Amsterdam etal. [16]
and Mompeo etal. [17]
b
d
18 Sensing Renal Nerve Activity Before, During andAfter Denervation: SyMap
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Fig. 18.2 Theoretical
framework for selective vs
global renal denervation: red
lines/dots represent “hot
spots”—pressor spots. These
are nerves that raise the blood
pressure when stimulated.
These spots are the ideal
targets of renal denervation.
Green line/spots represent
“cold spots”—inhibitory
spots, which lower the blood
pressure when stimulated.
The nerve bers in yellow are
neutral in their contribution
for blood pressure regulation
and do not show
hemodynamic effects when
stimulated. Adapted with
permission from Fudim etal.
[18]
183
types, numbers and sizes, as well as their distance from the
lumen in the proximal and distal segments of renal artery
mainstream and branches. Several recent studies [19–25]
have illustrated BP responses to renal nerve stimulation corresponding to the different nerve distributions around the
renal artery providing convincing evidence for the rationale
of renal mapping via renal nerve stimulation. Regarding the
concept of different BP responses to discrete site stimulations, we have demonstrated a substantial reduction in both
BP [20, 26] and serum norepinephrine levels in Chinese
Kunming dogs, a canine model with a spontaneous high
sympathetic tone, after ablating the sites which caused signicant rises in BP evoked by renal nerve stimulation, and
we conrmed that the BP-lowering effects were proportional
to the increases in BP by the stimulation. Histological evidence implied that these sites were innervated by nerve bundles containing sympathetic bers [19, 20] and that the
amplitudes of increases in BP to renal stimulation were proportionally determined by the total area and number of renal
nerves in stimulated sites (Fig.18.3). Renal stimulation can
be also used to assess whether a successful RDN is achieved.
After a successful RDN, BP response to stimulation should
be signicantly blunted; otherwise, it suggests an inadequate
denervation at the target sites and a second ablation on the
same site may be needed.
Thus, renal nerve stimulation and changes in BP in
response to the stimulation have been believed to have very
promising potential for mapping renal nerves in order to
selectively denervate sympathetic nerves and avoid futile
ablations.
Using BP Response Patterns toIdentify Hot
Spots, Cold Spots andNeutral Spots
Based on the heterogeneous physiology of sympathetic and
parasympathetic bers, variant proportions of sympathetic
and parasympathetic bers produce different phenotypes of
BP responses when stimulated. As we have discussed previously, [20] the same bundle may contain different types of
nerves such as sympathetic and parasympathetic (or sympathetic inhibitory) bers. The changes of BP in response to
electronic stimulation are an integrated physiological event,
depending upon which nerve bers are dominant at this particular site. If a parasympathetic dominant site is denervated,
it may partly neutralize the BP drop caused by sympathetic
denervation or even augment the BP.Thus, we propose that
the net effects of RDN on BP are related to the balance
between the sympathetic and parasympathetic nerve bers in
the ablated areas. Identication of BP patterns when stimulated could be key for renal mapping and selective RDN.
Animal Data
In animal studies, we [19] observed at least ve patterns of
BP responses which might potentially help us to distinguish
sympathetic or parasympathetic-dominant sites (Fig.18.4).
Pattern 1 BP immediately increased to its plateau in
response to renal nerve stimulation, maintained at a steady
and elevated status during stimulation indicating that renal
184
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J. Wang et al.
a
b
cde
Fig. 18.3 Difference in nerve distribution between strong-response
site (SRS) which increased blood pressure signicantly when stimulated, and weak-response site (WRS) which increased blood pressure
much less when stimulated. (a, b) Representative Masson staining
image for SRS and WRS.The red arrows indicated renal nerve bundle,
sympathetic nerves are dominant at this site. We also presumed that electrical stimulation signals were transmitted to
the central nerve system (CNS) via afferent bers and
increased central sympathetic activity, leading to an
increasing central sympathetic output to the entire body. It
caused a series of physiological effects, including peripheral
vasoconstriction, increases in myocardial contractility and
cardiac output, resulting in BP elevation. Efferent nerve
bers in the same bundle were also simulated; the efferent
sympathetic signals to kidneys participated in the elevation
of BP by renal artery contraction, release of renin from juxtaglomerular cells, and by increasing tubular sodium and
water reabsorption. Overall, this pattern of BP response represents a hot spot and an ablation is needed.
According to the character of increased BP response and
its quick response to stimulation, we named this pattern as
Sympathetic Dominant/Rapid Response. A typical original
tracing of BP in this pattern is shown in Pattern 1, Fig.18.4.
and the black arrows indicated ablation area. The total area (c)/number
(d) of renal nerves in SRS were greater than that in WRS.There was no
difference in distance (e) from lumen to nerve between SRS and
WRS.Adapted with permission from Liu etal. [20]
Pattern 2 BP transiently decreased below baseline and then
increased to achieve a steady and elevated status above baseline in responses to renal stimulation. We believe that this
pattern represents simultaneous activation of sympathetic
and vagal nerves. Because the transmitted speed of vagal
bers to the CNS is faster than that of afferent nerves, the BP
rst decreases and then gradually increases. The net effect
results in elevated BP, indicating that the impacts of sympathetic nerves on BP are more dominant than those of vagal
nerves. This site is a hot spot and should be ablated.
Because of the increased but delayed elevation of BP, this
pattern is named as Sympathetic Dominant/Slow Response,
shown in Pattern 2, Fig.18.4.
Pattern 3 BP immediately decreased below baseline in
response to renal stimulation and maintained at the low level
in a steady status during the stimulation. This pattern repre-
18 Sensing Renal Nerve Activity Before, During andAfter Denervation: SyMap
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Fig. 18.4 The different types
of blood pressure patterns in
responses to renal stimulation
in dogs. Adapted from Tan
etal. [19]
185
sents a site with dominant parasympathetic nerves, which
belongs to a cold spot and should not be ablated. Ablation of
such sites may lead to inhibition of parasympathetic nerve
activity and promotion of sympathetic nerve activity, resulting in BP elevation.
We named this pattern as Parasympathetic Dominant/
Rapid Response and an example of such a pattern is shown
in Pattern 3, Fig.18.4.
Pattern 4 BP transiently decreased below baseline in
response to renal stimulation and then went up but stayed a
level below baseline during the stimulation. This pattern of
BP also represents simultaneous activation of sympathetic
and parasympathetic nerves; however, the integrated effects
of these two nerve types maintain BP at a low level, indicating the dominant function of parasympathetic nerves. This is
a cold spot and should not be ablated.
Since BP achieves a low level at a steady state in a slow
manner, the pattern is named as Parasympathetic Dominant/
Slow Response, an example is shown in Pattern 4, Fig.18.4.
Pattern 5 BP uctuated around the baseline level in
response to renal stimulation but the uctuation was within
5mmHg beyond or below baseline during the stimulation.
This pattern represents a site in which there is no renal nerve
or a well-balanced and integrated function between sympathetic and parasympathetic nerves. Since BP did not change,
this site plays a minor role in BP regulation and, therefore,
presents a neutral spot and should not be ablated.
This pattern of BP is named as Neutral Response. An
example of this pattern is shown in Pattern 5, Fig.18.4.
Preliminary Human Data
BP response patterns due to renal stimulation are more complicated in a clinical setting. We have observed at least six
different patterns in responses to renal stimulation representing hot, cold and neutral spots, respectively. To best illustrating these patterns, graphs are shown in Fig.18.5. Here, the
elevation or reduction in BP was dened as the change of
systolic BP (SBP) ≥5mmHg from baseline.
Pattern 1: SBP is directly increased from baseline and main-
tained at an elevated level. This pattern is easily assessed
as a hot spot and needs to be ablated.
Pattern 2: SBP uctuated in the manner of repeatedly increas-
ing and then decreasing, or vice versa; however, the overall increases in SBP were above baseline more than
5mmHg. We believe that baroreex plays a big role in the
uctuations of BP. This is a hot spot and needs an
ablation.
Pattern 3: SBP transiently decreased below baseline and then
increased beyond baseline, and was maintained at an elevated steady level. This is a hot spot and needs to be
ablated.
Pattern 4: SBP is persistently decreased below baseline dur-
ing renal stimulation. This is a cold spot and ablation
should be avoided.
Pattern 5: SBP transiently increased beyond baseline then
decreased persistently below baseline when renal stimulation was performed. This is a cold spot and ablation
should be avoided.
186
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Fig. 18.5 The different types
of BP patterns in responses to
renal stimulation in human
J. Wang et al.
Pattern 6: SBP did not change much in response to renal
stimulation and uctuated around baseline. This is a neu-
tral spot and should also be avoided.
Apparently, the response patterns of BP to renal stimulation
in humans are more complicated than in animals. Although
the underlying mechanisms responsible for these patterns are
not fully understood and need to be further examined; analyzing and distinguishing these BP response patterns to renal
stimulation will help operators to identify nerve types and
determine sites that should or should not be ablated.
Renal Mapping andAblation System
The combined renal mapping and ablation system developed by SyMap Medical (Suzhou), Ltd. (Suzhou, China)
consists of a dedicated electronic mapping/ablation
SyMapCath I™ catheter and a SYMPIONEER S1™
Stimulator/Generator [27]. The stimulation/ablation
catheter has a steerable tip and is within a sheath that can
be manipulated to go forward/back and turn up to 90
degrees via a catheter handle. The sheath can be used for
contrast injection (Panel a, Fig.18.6) and the design provides operators convenience without using additional
accessories. The stimulator/generator can perform both
electronic stimulation and RF ablation with the same
catheter (Panel b, Fig.18.6). This system could facilitate
appropriate patient selection through screening for candidates whose BP is driven by renal sympathetic nerve
activity. In addition, it would allow operators to target
only optimal ablation sites (hot spots/sympatho-stimulatory) while minimizing damage to cold spots/sympathoinhibitory sites, with documentation of technical success
through the loss of systemic BP changes when stimulated
again after RDN.
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