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10 Obstructive Sleep Apnea, Resistant Hypertension andRenal Denervation
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109
the patients with mild and moderate-to-severe sleep apnea.
Decreases in AHI at 3 months (non-signicant) and at
6months (with a tendency towards signicance) after RDN
were noted (median 16.3 events/h before RDN versus median
4.5 events/h; p=0.059). Also decreases in oxygen desaturation indices (ODI) at 6months (median 13.0 events/h before
RDN versus median 8.7 events/h; p=0.11) and decreases in
median Epworth Sleepiness Scale score at 6 months (9.00
points versus 7.00 points; p< 0.05) were reported. In summary, in 8 of 10 patients an improvement in AHI was observed
at 6month (Fig.10.2). There were 2 patients with mixed sleep
apnea. In one of them, a reduction in sleep apnea indices was
also observed with a change in AHI -30.5 events per hour at
6months. In patients with improvements in AHI, a signicant
decrease in 24-h, daytime, and nighttime ABPM levels was
observed, the latter being most pronounced (median:
−8/−4mm Hg, −12/−5mmHg and-10/−8mm Hg for 24-h,
daytime, and nighttime, respectively; p<0.05 for all).
Along with the blood pressure reduction and sleep apnea
course improvement signicant decreases in plasma glucose
concentration 2 h after glucose administration at 3 and at
6months (median 7.0mmol/dL versus median 6.4, mmol/dL
at 6 months; p < 0.05) and in hemoglobin A1C level at
6months (median 6.1% versus median 5.6%; p<0.05) were
demonstrated. This study conrmed that RDN lowers blood
pressure in patients with resistant hypertension [40, 41] and
supported the work of Mahfoud etal. documenting that RDN
in humans improves indices of insulin action and glucose
metabolism [42]. However, this publication extended previous work by documenting that the blood pressure and meta-
bolic benets of renal denervation include patients with
sleep apnea and improve the course of the disease.
The second study was a small, single center, randomized
trial which recruited 60 patients with true resistant hypertension coexisting with moderate-to-severe OSA (apnea/hypopnea index ≥15), who were randomly allocated to RDN or
control group [39]. The primary end point was the ofce systolic blood pressure at 3months and the secondary end points
included the apnea/hypopnea index and biochemical measurements at 3months. Signicant reductions in ofce and
ambulatory BP were observed after RDN as well as signicant decrease in OSA severity (apnea/hypopnea index, 39.4
versus 31.2 events per hour; P=0.015) (Fig.10.3). Betweengroup difference in apnea/hypopnea index change was signicant at 0.05. At 6months in the RDN group, reductions in
ofce and ambulatory BP were sustained. Interestingly,
RDN also signicantly reduced night heart rate, a phenomenon which was not observed in control subjects. However, in
contrast to previous study investigators did not observe any
differences in insulin and glucose metabolic variables in
follow-up in both groups. A major limitation of this study
was lack of sham treatment. The trial conrmed that RDN
lowers both, ofce and ambulatory BP in patients with resistant hypertension and OSA, and this was accompanied by
improvement of the clinical severity of OSA.
Based on these two study results it should be emphasized
that RDN inuences key mechanisms regulating sympathetic
activation. The efferent sympathetic renal nerves can affect
control of renal vascular resistance, increase renin release,
and regulate sodium and water excretion [12]. The afferent
Fig. 10.2 Changes of AHI at
3 and 6months after
denervation. Data of
individual cases. (Figure
reused with permission from
the rst edition of the book)
110
a
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A. Witkowski and J. Kądziela
b
Fig. 10.3 Ofce blood pressure (BP) changes (a) and ambulatory 24-h average BP changes (b) (Fig. 10.2 from article Warchol-Celinska E
etal.Hypertension 2018;72:381–90)
renal nerves enhance the activity of the sympathetic nervous
system. It has been also suggested that, in conditions of highsodium dietary intake, activation of the afferent renal nerves
contributes to the arterial baroreceptor-mediated suppression
of efferent sympathetic renal nerves in the overall goal of
preventing sodium retention and maintaining water and
sodium homeostasis [12, 43]. Therefore, RDN in patients
with resistant hypertension and OSA might attenuate the
effects of sympathoactivation additionally and independently
of CPAP treatment. Last, it needs to be considered that the
fall in BP may itself contribute to the attenuation of sleep
observational and one randomized study have shown that
catheter-based renal sympathetic denervation may not only
lower systolic blood pressure in resistant hypertensive
patients with sleep disordered breathing but also improve
sleep apnea severity, but the number of recruited patients was
small.
Renal sympathetic denervation may conceivably be a
potentially useful therapeutic option for this subset of
patients, however large, multicenter, sham-controlled, randomized clinical trial is needed to nally conrm these
encouraging data.
apnea.
Conict of Interest Statement Adam Witkowski– consul-
tancy agreement with Medtronic, investigator‘s fees from
Summary
ReCor.
Jacek Kądziela –consultancy and proctoring fees from
Obstructive sleep apnea is a potential independent risk factor
Medtronic, investigator’s fees from ReCor.
for cardiovascular events, including ischemic heart disease,
heart failure, stroke and death. In addition, obstructive sleep
apnea is the most common disease associated with resistant
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Potential Role ofRenal Denervation
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inManagement ofAtrial Fibrillation
TimA.Fischell
11
Introduction
The autonomic nervous system plays a central role in the
pathogenesis of multiple cardiac arrhythmias, including
atrial brillation and ventricular tachycardia [1–7].
Autonomic modulation, via renal sympathetic denervation,
has the potential to induce neural remodeling achieving a
therapeutic benet in arrhythmia control in atrial brillation
[8, 9]. Hypertension is also common in patients with brillation, and may contribute to the clinical outcomes and
response to therapies, and may be modulated by renal sympathetic denervation.
Pulmonary vein isolation (PVI) is used in many patients
who have unsatisfactory results with drug therapy for atrial
brillation. Although AF ablation therapy can be effective,
there are often suboptimal short-term and long-term results,
and with a high rate of AF recurrence with one-year [10].
The combination of renal denervation, as an adjunct therapy
to pulmonary vein isolation [9, 11–17], or as a stand-alone
intervention to reduce AF burden [18, 19] represent a promising new frontier for renal denervation. This chapter will
review the background and scientic evidence that support
the use of sympathetic nervous system modulation using
renal sympathetic denervation as an adjunct to pulmonary
vein isolation for the management of patients with paroxysmal or persistent atrial brillation.
Role oftheAutonomic Nervous System
inAtrial Fibrillation
Sympathetic nerve activation leads to the release of norepinephrine (NE) as the primary adrenergic neurotransmitter.
Norepinephrine is synthesized in neural cell bodies, transported and concentrated in vesicles in nerve varicosities
T. A. Fischell (*)
Borgess Heart and Vascular Center, Kalamazoo, MI, USA
e-mail: taf@ablativesolutions.com
adjacent to adrenergic receptors, where it is released by
nerve depolarization through a Ca2+-dependent process. NE
can promote or create an atrial substrate that may promote
AF, related to cardiomyocyte Ca
“business” of beta-adrenergic activation in the heart is to
enhance cardiac output during “ght-or-ight” reactions.
Accordingly, beta-adrenergic stimulation enhances virtually
all processes controlling Ca2+-entry in the heart. Activation
of the autonomic nervous system, and localized release of
norepinephrine, can induce signicant changes in atrial electrophysiology, and can incite or promote atrial tachyarrhythmias, including atrial tachycardia (AT) and atrial brillation
(AF) via complex Ca++ handling pathways, and related to
the interaction with cholinergic activation. Adrenergic activation may promote enhanced automaticity, early or delayed
afterdepolarization-associated triggered activity, and effective refractory period heterogeneity [6]. All of these electrophysiologic mechanisms can promote the triggering and/or
maintenance of atrial brillation [6].
The relationship between abnormal autonomic innervation and AF has been observed in both animal models, and
in humans [6, 20–22]. In a number of animal models, the
promotion of increased sympathetic nerve density is associated with creation of AF [23]. Atrial nerve sprouting and
sympathetic hyperinnervation also occur after ventricular
myocardial infarction and are associated with increased
incidence and duration of AF [24]. Atrial sympathetic nerve
densities are also signicantly increased in in patients with
chronic AF [25].
It is clear that autonomic nerve activity plays an important
role in the initiation and maintenance of AF.Based upon the
important contribution of enhanced adrenergic input to the
promotion of AF, it is not surprising that interventions that
modulate or reduce autonomic innervation or outow have
been shown to reduce the incidence of spontaneous or
induced atrial arrhythmias, and suggest that neuromodulation may be helpful in controlling AF [2, 3, 11–18].
Potential therapeutic approaches to modulate sympathetic
outow in the management of AF include ganglionated
2+
-handling [6]. The main
© 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_11
113
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T. A. Fischell
plexus ablation [2, 3], vagal nerve stimulation [26, 27], baroreex stimulation [27], cutaneous stimulation and renal sympathetic denervation [11–15, 28]. This chapter will focus
upon the evidence relevant to renal denervation, as a means
to alter sympathetic activity, and its potential therapeutic
effect(s) in the management of atrial brillation.
Studies ofRenal Denervation
fortheManagement ofAtrial Fibrillation
A number of recent, carefully controlled clinical trials suggest that renal sympathetic denervation through an endovascular approach is effective in reducing blood pressure both in
patients off medications [29, 30] and in patients with drug
resistant hypertension [31–33]. There are limited clinical
data showing that renal denervation can reduce sympathetic
nerve activity, possibly via an up-regulation of alpha-2 receptors in the nucleus tractus solitarius in the medulla [34]. A
reduction of sympathetic outow may explain the reduction
of blood pressure in some patients. The same effects may
also be useful in controlling AF. Blood pressure lowering,
may itself, via effects on structural and electrical remodeling, and/or hemodynamic lling pressures, may reduce the
propensity for atrial brillation. [1, 7]
In the past 8years a number of randomized clinical trials
have evaluated the safety and efcacy of RDN in the management and control of atrial brillation [11–19]. Overall,
there have been relatively consistent and encouraging, positive data from these trials, suggesting a role for RDN in the
management of AF.In the following section we will review
the clinical trials examining the role of RDN in the management of atrial brillation.
Russian Study
The rst meaningful study of RDN in AF was published in
2012 [11]. It was a small randomized, single center, clinical
trial intended to evaluate the incremental effects of renal
denervation following pulmonary vein ablation. The aim of
this prospective randomized study was to assess the impact
of renal artery sympathetic denervation in patients with a
history of refractory AF, and drug-resistant hypertension
referred for pulmonary vein isolation (PVI). Patients with a
history of symptomatic paroxysmal or persistent AF refractory to ≥2 antiarrhythmic drugs and drug-resistant hypertension (systolic blood pressure > 160 mm Hg despite triple
drug therapy) were eligible for enrollment. Subjects were
randomized to PVI only or PVI with renal artery denervation. RDN was performed relatively aggressively with the
original Simplicity monopolar RF ablation catheter, and with
~6 RF ablations per artery. All patients were followed
≥1year to assess maintenance of sinus rhythm and to monitor changes in blood pressure. Twenty-seven patients were
enrolled. Fourteen subjects were randomized to PVI only,
and 13 were randomized to PVI with renal artery denervation. At the end of the follow-up, there was a signicant
reduction in systolic (from 181±7 to 156±5, p<0.001) and
diastolic blood pressure (from 97±6 to 87±4, p<0.001) in
patients treated with PVI with renal denervation. There was
no signicant BP change in the PVI only group. Nine of the
13 patients (69%) treated with PVI with renal denervation
were AF-free at the 12-month post-ablation follow-up examination versus 4 (29%) of the 14 patients in the PVI-only
group (p = 0.033). The investigators concluded that renal
artery denervation reduces systolic and diastolic blood pressure in patients with drug-resistant hypertension and reduces
AF recurrence when combined with PVI.Obviously, there
are limitations for this study, including primarily, that this
was a small size, single center study.
Kiuchi Study
The Kiuchi was a single center study that examined the addition of renal sympathetic denervation to pulmonary vein isolation (PVI) on the recurrence of AF in subjects with chronic
kidney disease and uncontrolled hypertension [13]. They
studied the relative effects of RSD versus spironolactone
50mg/day, in combination with PVI,to reduce systolic blood
pressure, AF recurrence, and AF burden in patients with a
history of paroxysmal AF and mild CKD.This was a prospective, longitudinal, randomized, double-blind study. The
subjects were randomly divided into two groups (PVI+spironolactone, n = 36, and PVI + RSD, n = 33). All of the
patients were followed for 1year to assess maintenance of
sinus rhythm. The main nding was that more patients in the
PVI+RSD (61%) than in the PVI+spironolactone group
(36%) were AF-free at one-year of follow-up, P=0.0242.
The mean AF burden was lower in the PVI+RSD group as
compared to PVI + spironolactone group, at 12 months:
∆=−12% (P<0.0001). The concluded that PVI+RSD was
safe and appeared to be superior to PVI+spironolactone in
BP reduction, augmentation of AF event-free rate, reduction
of AF burden, and improvement of renal function.
Eradicate AF
The Evaluate Renal Denervation in Addition to Catheter
Ablation to Eliminate Atrial Fibrillation (ERADICATE-AF)
trial was an investigator-initiated, multicenter, single-blind,
randomized clinical trial conducted at 5 referral centers for
catheter ablation of atrial brillation in the Russian
Federation, Poland, and Germany. This study is perhaps
11 Potential Role ofRenal Denervation inManagement ofAtrial Fibrillation
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115
the largest and most compelling study suggesting a therapeutic benet of renal denervation in the management of
atrial brillation [12]. The objective of this clinical trial was
to determine whether renal denervation when added to pulmonary vein isolation enhances long-term antiarrhythmic
efcacy. A total of 302 patients with paroxysmal atrial brillation and with hypertension despite taking at least 1
antihypertensive medication, and who were referred for
catheter-based AF ablation were enrolled from April 2013 to
March 2018. Patients were randomized to either pulmonary
vein isolation alone (n= 148) or pulmonary vein isolation
plus renal denervation (n=154). Complete pulmonary vein
isolation was carried out to achieve an end point of elimination of all pulmonary vein potentials. Renal denervation was
performed using an irrigated-tip ablation catheter delivering
radiofrequency energy to discrete sites in a spiral pattern
from distal to proximal in both main renal arteries. The primary end point was freedom from atrial brillation, atrial
utter, or atrial tachycardia at 12 months of follow-up.
Secondary end points included blood pressure control at 6
and 12months. Of the 302 randomized patients completed
the trial, all successfully underwent their assigned procedures. Freedom from atrial brillation, utter, or tachycardia
at 12months was observed in 84 of 148 (56.5%) of those
undergoing pulmonary vein isolation alone and in 111 of 154
(72.1%) of those undergoing pulmonary vein isolation plus
renal denervation (P= .006). Mean systolic blood pressure
from baseline to 12months decreased from 151mm Hg to
147mm Hg in the isolation-only group and from 150mm Hg
to 135 mm Hg in the renal denervation group (betweengroup difference, −13mm Hg; P<.001). Procedural complications occurred in 7 patients (4.7%) in the isolation-only
group and 7 (4.5%) of the renal denervation group. The
authors concluded that among patients with paroxysmal
atrial brillation and hypertension, renal denervation added
to catheter ablation, compared with catheter ablation alone,
signicantly increased the likelihood of freedom from atrial
brillation at 12months.
(51.8%) in the PVI group. RDN+PVI was associated with a
lower incidence of AF recurrence (RR 0.62, P<.001). The
incidence of complications was similar between the two
groups, (7/241 (2.9%) in the RDN+PVI group and 8/237
(3.4%) in the PVI group; P= .77). The authors concluded
that RDN in addition to PVI, is associated with reduced
12-month AF recurrence with similar procedure-related
complications compared to PVI alone.
AFFORD Study
The AFFORD study was a small prospective single center
study to examine whether renal sympathetic denervation
(RDN), using the Enlighten RF device, decreases atrial brillation (AF) burden in hypertensive patients with symptomatic AF. AF burden was evaluated at at 6- and 12-month
follow-up, as measured using an implantable cardiac monitor (ICM). A total of 20 patients with symptomatic paroxysmal or persistent AF and primary hypertension with a mean
ofce systolic blood pressure (BP) of > 140 mmHg were
enrolled. After enrolment, an ICM was implanted 3months
prior to renal denervation to monitor AF burden. The AF burden in min/day decreased from a median (IQR) of 1.39 preRDN to 0.67 at 6months (p=0.64) and to 0.94 at 12months
(pre-RDN vs. 12months; p=0.03). The quality of life also
improved signicantly at both 6months and 12months as
compared to pre-RDN.Ofce BP decreased signicantly at
12-month follow-up (− 20±19/− 7 ±10mmHg), p <0.01)
as compared to pre-RDN. Ambulatory BP decreased
− 7±16/− 3±9mmHg (p>0.05) at 12-month follow-up as
compared to pre-RDN.The small AFFORD study suggests
that RDN might be able to decrease AF burden as measured
using an ICM, and with a positive effect on QOL.This is one
of the only studied to evaluate the effects of RDN on atrial
brillation in hypertensive patients who are not undergoing
pulmonary vein (AF) ablation therapy.
Pranata- Meta Analysis
Pranata etal. performed a systematic literature search, with a
meta-analysis of randomized and controlled clinical trials, to
evaluate the additive therapeutic effects of RDN when combined with pulmonary vein isolation (PVI) in patients with
hypertension and atrial brillation [16]. In this analysis of
ve clinical trials, the primary outcome was AF recurrence
dened as AF/atrial utter (AFL)/atrial tachycardia (AT)
≥30seconds at 12-month follow-up. The secondary outcome
was procedure-related complications. They analyzed the
data from 568 subjects from ve studies. AF recurrence was
90/280 (32.1%) in the RDN + PVI group and 142/274
Summary
The sympathetic nervous system plays a key role in the triggering and maintenance of atrial brillation. Both preclinical and clinical studies suggest that suppression, or
modulation of central sympathetic nerve activity may reduce
the incidence and/or the sustainability of atrial brillation.
There is an accumulating body of evidence that suggest that
renal sympathethic denervation can favorably inuence both
the recurrence of atrial brillation when combined with pulmonary vein isolation (PVI), and AF burden in patients with
recurrent AF and poorly controlled hypertension. In addition, all of these recent randomized studies continue to demonstrate a BP lowering effect in patients undergoing
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T. A. Fischell
catheter-based renal denervation, compared to control
patients. The acceptance of renal denervation as a standard
of treatment for the management of patients with AF, and
hypertension, undergoing PVI (ablation) intervention awaits
the completion of additional, large and pivotal randomized
clinical trials, leading to regulatory approval(s).
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Potential ofRenal Denervation
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intheManagement ofVentricular
Arrhythmias
EmanuelM.Ebin andVenkatakrishnaN.Tholakanahalli
12
Introduction
Ventricular tachyarrhythmias (VAs) account for a signicant
portion of sudden cardiac death. Recent population studies
demonstrate a burden of disease affecting as many as one-inone-thousand adults less than 55years of age with a doubling of that rate for populations over 65 years old [1].
Antiarrhythmic therapy(AAD) has been a mainstay of treatment with some of the rst published prospective data dating
back to the late 1960s [2]. In the 1980s, a direct surgical
approach was explored and with the explosion of radiofrequency ablation in the 1990s, this became the mainstay as
an adjunct to ICD therapy. Despite advancement and
improvement in the ablation technologies over the last
30years, the electrophysiologist will encounter patients with
VAs that are refractory to both medical therapy and catheter
ablation. This leads to consideration of advanced therapies
including heart transplantation which is not readily available
worldwide and ventricular assist devices. Cardiac sympathetic denervation (CSD) and neuraxial modulation has
shown some hope in the management of ventricular arrhythmias [3]. One such well-established modality is bilateral cardiac sympathectomy involving resection of the lower half of
the stellate ganglion and T2 to T4 resection along with the
nerve of Kuntz [4]. Further renal denervation (RDN) has
been explored as a modality towards approaching neuraxial
modulation in suppressing VAs.
Throughout this chapter, we will review the rationale for
renal denervation to treat VAs and explore prior animal studies and human case series. We will conclude with future
directions of renal denervation as an adjunct to current ther-
E. M. Ebin
University of Minnesota, Minneapolis, MN, USA
V. N. Tholakanahalli (*)
University of Minnesota, Minneapolis, MN, USA
Minneapolis VA Health Care System, Minneapolis, MN, USA
e-mail: thola001@umn.edu
apy as well as a proposed work-ow when considering
advanced therapies to treat refractory VAs.
Rationale forRenal Denervation
While catheter ablation has remained the mainstay of curative therapy for ventricular arrhythmias, published data demonstrates varying success rates ranging from as little as 38%
in non-ischemic cardiomyopathy to 77% in patients with
ischemic cardiomyopathy [5, 6]. Indeed, while targeting discrete channels in ischemic cardiomyopathy has improved
over the years, this has not been matched with catheter ablation of non-ischemic cardiomyopathies. Often, progression
of disease in both ischemic and non-ischemic cardiomyopathies lead to increased substrate burden and consequently,
new and worsening ventricular arrhythmias. This may lead
to substrate that is difcult to target, particularly with midseptal or epicardial channels that require advanced ablative
techniques not available to smaller centers.
Sympathetic input has long been established in the induction, participation and propagation of VAs. Medical therapies including beta-blockers and ACE-inhibitors are a
mainstay of treatment for cardiomyopathies and owe their
success, in part, to their reduction of sympathetic tone on the
cardiac myocytes. AADs, though helpful in suppressing
VAs, are overshadowed by the side effects and tolerance over
time.
Acutely, trans-epidural anesthesia (TEA) is useful in suppressing VAs in patients who present with VA storm. This
technique involves short-term use of an anesthetic agent in
the epidural space to suppress refractory ventricular arrhythmias as well as catecholaminergic polymorphic ventricular
tachycardia (CPVT) [3, 7]. These methods, while effective,
are temporizing measures. Surgical denervation of the myocardium has been reported in the literature as early as 1921
[8] although it was not for another 40years before regaining
traction in the literature. This technique utilizes a surgical
approach to either bilateral or left cardiac sympathetic dener-
© 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_12
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