REVIEW

Renal denervation: effects on atrial electrophysiologyand arrhythmias

Dominik Linz • Arne van Hunnik • Christian Ukena • Sebastian Ewen •

Felix Mahfoud • Stephan H. Schirmer • Matthias Lenski •

Hans-Ruprecht Neuberger • Ulrich Schotten • Michael Bohm

Received: 18 January 2014 / Accepted: 26 February 2014

� Springer-Verlag Berlin Heidelberg 2014

Abstract Atrial fibrillation (AF) is the most common

sustained arrhythmia and is associated with significant

morbidity and mortality. Currently, atrial endocardial cath-

eter ablation, mainly targeting focal discharges in the pul-

monary veins, is the most widely used interventional

treatment of drug-refractory AF. Despite technical

improvements, results are not yet optimal. There is ongoing

search for alternative and/or complementary interventional

targets. Conditions associated with increased sympathetic

activation such as hypertension, heart failure and sleep apnea

lead to structural, neural and electrophysiological changes in

the atrium thereby contributing to the progression from

paroxysmal to persistent AF and increasing recurrence rate

of AF after PVI. Until now, interventional modulation of

autonomic nervous system was limited by highly invasive

techniques. Catheter-based renal denervation (RDN) was

introduced as a minimally invasive approach to reduce renal

and whole body sympathetic activation with accompanying

blood pressure control and left-ventricular morphological

and functional changes in resistant hypertension. This

review focuses on the potential atrial antiarrhythmic and

antiremodeling effects of RDN in AF patients with hyper-

tension, heart failure, and sleep apnea and discusses the

possible role of RDN in the treatment of AF.

Keywords Atrial fibrillation � Renal denervation �Hypertension � Heart failure � Sleep apnea

Introduction

Atrial fibrillation (AF) is prevalent in 1–2 % of the general

population, and the number of affected individuals is

expected to double or triple within the next two to three

decades due to aging of European populations [1–4]. AF

doubles mortality and causes marked morbidity and more

importantly reduced quality of life [5–13]. Currently,

catheter-based isolation of pulmonary veins (PVI) is the

most widely used interventional approach for treatment of

drug-refractory AF. This therapeutic concept, largely based

on the work of Haıssaguerre et al. [14], has been introduced

over two decades ago and mainly targets focal discharges

in the pulmonary veins. However, this treatment modality

is recommended as class I indication for symptomatic AF

refractory to at least one antiarrhythmic medication [15].

Clinical trials reported an efficacy of 66–89 % [16] but the

real-world cohort validation through large surveys dis-

closed even lower success rates of 55–70 % [17]. There are

several reasons for recurrent AF after PVI. The pulmonary

veins often do not remain isolated [18], and recurrence rate

of AF after PVI is higher in patients with particular

comorbidities such as congestive heart failure, hyperten-

sion and obstructive sleep apnea (OSA) [19]. Congestive

heart failure [20], OSA [21] and hypertension [22] have

been shown to lead to anatomical and structural changes in

the atrium characterized by atrial enlargement, regions of

scarring, fibrosis and abnormalities of conduction (struc-

tural remodeling) increasing the likelihood of reentry cir-

cuits and thereby the occurrence and stabilization of AF

[23]. Importantly, this structural atrial remodeling mainly

D. Linz (&) � C. Ukena � S. Ewen � F. Mahfoud �S. H. Schirmer � M. Lenski � H.-R. Neuberger � M. Bohm

Klinik fur Innere Medizin III Kardiologie, Angiologie und

Internistische Intensivmedizin, Universitatsklinikum des

Saarlandes, Kirrberger Str. 1, Geb. 40, 66421 Homburg/Saar,

Germany

e-mail: dominik.linz@uks.eu

A. van Hunnik � U. Schotten

Cardiovascular Research Institute Maastricht (CARIM),

Maastricht, The Netherlands

123

Clin Res Cardiol

DOI 10.1007/s00392-014-0695-1

occurs independently of focal discharges in the pulmonary

veins and can, therefore, not be sufficiently influenced by

catheter ablation limited to the pulmonary veins. In addi-

tion to mechanisms such as atrial stretch and atrial

remodeling [23], also the activity of the autonomic nervous

system being elevated in hypertension [24], heart failure

[25] and OSA [26] has been suggested to contribute to the

development of AF [27].

Role of sympathetic nervous system for the initiation

and perpetuation of AF

At the cellular level, norepinephrine, the neurotransmitter of

the sympathetic nervous system, is released from postgan-

glionic neurons in response to sympathetic stimuli activating

beta-receptors. The stimulatory beta-adrenergic response is

initiated via Gas, leading to the activation of adenyl cyclase

and subsequent protein kinase A-mediated phosphorylation

of L-type calcium channels, troponin I, and phospholamban,

resulting in increased calcium influx. Sarcoplasmic reticu-

lum calcium channels (called ryanodine receptors) release

calcium in response to transmembrane calcium entry.

Ryanodine receptors are normally closed during diastole but

can open if they are functionally defective or if the sarco-

plasmic reticulum is calcium overloaded [23, 28]. Calcium is

partly extruded to the extracellular space by the Na?/Ca2?

exchanger (NCX). The NCX is electrogenic due to the 3:1

stoichiometry (3 Na? ions are exchanged for 1 Ca2? ion), and

produces an inward current that underlies delayed afterde-

polarizations (DADs) related ectopic firing. Heightened

sympathetic tone induces focal discharges from pulmonary

veins, which have high concentration of adrenergic and vagal

nerve endings [29]. In addition, alpha-adrenergic stimulation

inhibits the transient outward current Ito. On the other hand,

beta-adrenergic receptor activation increases different re-

polarizing ion currents. As a net result of sympathetic stim-

ulation, the plateau potential of the action potential is

increased [23], while the total action potential duration is

unaffected or even decreased [30]. In addition, sympathetic

activation results in neurohumoral responses involving, e.g.,

the renin–angiotensin–aldosteron system activating profib-

rotic pathways, leading to atrial structural changes [23].

Shortened atrial refractoriness during AF (electrical

remodeling) together with local conduction disturbances

may facilitate occurence of reentry circuits.

Several observations in vivo suggest that the autonomic

nervous system plays an important role in the initiation and

the maintenance of AF. Sympathetic hyperinnervation is

reported in atria of dogs with rapid atrial pacing [31] and

Ogawa et al. [32] have shown increased sympathetic and

vagal nerve discharges before the onset of atrial arrhyth-

mias in dogs with pacing-induced congestive heart failure.

In experimental animal models, the beta-adrenergic ago-

nists (i.e. isoproterenol) in conjunction with rapid atrial

pacing have been successfully used to induce AF [33].

Interestingly, it has been shown that postoperative AF is

more common in patients after lung transplantation com-

pared to heart transplant recipients. Both groups have

functional pulmonary vein isolation, but cardiac autonomic

denervation only occurs after heart transplantation and may

exert an antiarrhythmic effect [34]. Beta-receptor blockade

by metoprolol was effective in preventing recurrence of AF

after successful cardioversion [35].

Therefore, the modulation of autonomic nervous system

might be a promising target for intervention in AF patients.

Today, several strategies are available to modulate the

complex interaction between increased sympathetic activ-

ity and the heart. Previously, ablation of the ganglionated

plexi alone or together with PVI has been used in patients

with both paroxysmal and persistent AF with variable

success [36–38].

Renal denervation as a tool to modulate autonomic

nervous system

Renal sympathetic nerves are an interesting target for

intervention. Activation of renal efferent sympathetic nerve

fibers increases sodium and water retention, reduces renal

blood flow and elevates renin release from juxtaglomerular

apparatus, regulating blood pressure and renal perfusion

[39, 40]. The kidney, however, also has an extensive net-

work of afferent unmyelinated fibers that transmit impor-

tant sensory information to the central nervous system.

Afferent fibers from the kidney, which carry information

from renal chemo- and mechano-receptors, travel along

with the sympathetic nerves at the level of the kidney and

then enter the dorsal roots and project to regions of the

brainstem involved in cardiovascular control [39, 40].

Therefore, the kidney can be a source of increased sym-

pathetic activation under certain pathophysiological con-

ditions such as renal hypoxia.

Recently, a catheter-based approach has been developed

for renal sympathetic denervation (RDN) [41]. First-gen-

eration devices use radiofrequency pulses emitted from a

monopolar electrode positioned under fluoroscopic guid-

ance in each of the renal arteries. Mechanistically, it has

been observed that the procedure resulted in a 47 %

reduction of renal norepinephrine spillover measured with

a radiochemical tracer methodology using 3H-norepi-

nephrine [42, 43]. Interestingly, firing of single sympa-

thetic vasoconstrictor fibers (measured by single muscle

sympathetic nerve activity), a parameter of whole body

sympathetic activation was reduced by 37 % [44]. These

findings indicate that not just locally in the kidney, where

Clin Res Cardiol

123

the ablation procedure is performed, but also in the whole

body sympathetic activation can be reduced by RDN,

suggesting a combined modulation of efferent and afferent

signaling. RDN might influence atrial electrophysiology as

well as atrial structural remodeling processes by modula-

tion of autonomic nervous system, which might result in

antiarrhythmic effects. Clinical observations suggest that

particularly baseline blood pressure as well as baseline

heart rate are predictors of good response for RDN in terms

of blood pressure control. Whether these parameters can

also predict response to RDN in terms of arrhythmia res-

olution is unknown.

Atrial electrophysiological effects of renal denervation

RDN results in a reduction in heart rate and AV-con-

duction velocity in pigs [45] and in resistant hypertensive

humans [46]. In chloralose/urethane anesthetized pigs

[45], neither atrial effective refractory period nor P-wave

duration was influenced by acute RDN excluding relevant

changes in atrial refractoriness and atrial conduction

during sinus rhythm [45]. In addition, sensitivity of gan-

glionated plexi [47] was not modulated by RDN. In an

AF pig model with rapid atrial pacing, RDN reduced

duration of pacing-induced AF. However, AF-induced

electrical remodeling was not attenuated [45]. Interest-

ingly, in humans with AF as well as in anesthetized pigs

with AF induced by rapid atrial pacing, RDN reduces

heart rate during AF, which might reduce clinical symp-

toms in patients with AF [45]. Moreover, increased AF

inducibility, shortening and dispersion of atrial refracto-

riness as well as elevated plasma norepinephrine levels

were almost completely prevented by RDN in animals

subjected to stimulation of left stellate ganglion and rapid

atrial pacing for 3 h [48].

Antiremodeling effect of renal denervation

Different mechanisms of AF in ‘‘Hypertension’’, ‘‘Heart

failure’’ and ‘‘Sleep apnea’’, and potential targets of RDN

to show antiarrhythmic effects in the atrium are summa-

rized in Fig. 1.

Hypertension

Hypertension is one of the best established risk factors for

AF [49]. The higher the blood pressure, the greater the risk

for AF [50, 51]. Hypertension affects the atrium hemody-

namically because acute as well as chronic blood pressure

elevation can increase atrial stretch and result in atrial

dilation, together resulting in the promotion of an

arrhythmogenic substrate. Recently, Lau et al. [22] showed

in a sheep model that the hypertensive group developed a

progressive increase in mean arterial pressure, progressive

bi-atrial hypertrophy, atrial inflammation, and greater AF

inducibility, while mean effective atrial refractory periods

were prolonged [22]. In addition, activation of the renin

angiotensin system is increased in hypertension [52] and

has been shown to create arrhythmogenic atrial substrates.

Aldosterone causes a substrate for atrial arrhythmias

characterized by atrial fibrosis, myocyte hypertrophy, and

conduction disturbances in a rat model [53]. RDN has been

shown to significantly reduce systolic and diastolic blood

pressure in resistant hypertensive patients [42, 43, 54, 55].

In previous studies, RDN resulted in an improvement of

left-ventricular hypertrophy and diastolic function inde-

pendent from changes in blood pressure and heart rate in

resistant hypertensive patients [56], suggesting that this

may be a direct effect of modulating the autonomic ner-

vous system. Blood pressure reduction together with pre-

vention of ventricular and atrial remodeling by RDN may

attenuate the progression of AF to persistent AF, as

regression of left-ventricular hypertrophy has previously

been shown to be associated with decreased incidence of

new-onset AF in hypertensive patients [57]. However, all

these studies [42, 43, 54, 55] did not include a placebo

group. In order to address this problem the SYMPLICITY

HTN-3 trial was designed in the United States. SYM-

PLICITY HTN-3 is the first blinded, randomized, con-

trolled trial designed to evaluate the safety and

effectiveness of RDN with the investigational Symplicity

RDN system in patients with treatment-resistant hyper-

tension and systolic blood pressure higher than 160 mmHg.

The study randomized 535 treatment-resistant hypertension

patients in 87 medical centers. People receiving the

investigational treatment were compared with a sham-

control group that did not receive treatment, with all

patients continuing to take their blood pressure medica-

tions. This trial has incorporated a strict screening for

adherence for anti-hypertensive medications in these

patients. Unfortunately, patients were allowed to be upti-

trated only 2 weeks before the intervention and some

might not have been on a stable medication unlike in the

previous studies [42, 43, 54, 55]. The primary endpoints of

the study are the change in office blood pressure from

baseline to 6 months and incidence of major adverse

events. Further details about the SYMPLICITY HTN-3

Clinical Trial can be found on www.clinicaltrials.gov

(Identifier: NCT01418261). Surprisingly, on January 9,

2014, Medtronic announced that SYMPLICITY HTN-3

met its primary safety endpoint but failed to meet its pri-

mary efficacy endpoint. The definite results of the SYM-

PLICITY HTN-3 trial are urgently needed to finally judge

the effect of RDN on blood pressure control.

Clin Res Cardiol

123

Heart failure

Heart failure is associated with the development of a

proarrhythmic structural and electrical remodeling process

in the atrium [23, 58] and stimulation of the sympathetic

nervous system [59–61]. Circulating catecholamine con-

centrations, as marker of enhanced sympathetic activation,

are related to outcome [59, 60], but are already increased in

asymptomatic left-ventricular function [61] providing evi-

dence that sympathetic stimulation contributes to the pro-

gression of heart failure syndrome [61]. Interestingly,

cardiac and renal spillover of norepinephrine is more clo-

sely associated with mortality than circulating catechol-

amine concentrations [62, 63]. The atrial remodeling

process observed in patients with heart failure are compa-

rable to the one observed in hypertensive heart disease. The

underlying pathophysiological link and the common path-

way for hypertension and heart failure to lead to AF is atrial

pressure and/or chronic volume overload as well as diastolic

ventricular dysfunction which may lead to atrial dilatation,

fibrosis, and electrical remodeling that finally provides the

stimulus and the substrates for the development of AF [23,

58]. Interestingly, chronic atrial volume overload in goats

with chronic AV block leads to progressive atrial dilatation,

prolongation of induced AF paroxysms, and local conduc-

tion delays even independent of increased atrial fibrosis

[64]. However, extrapolating the benefit of renal denerva-

tion in heart failure from hypertension studies should be

done with caution. Studies directly examining the use of

renal denervation to treat heart failure are sparse. A multi-

centre, randomized trial (RE-ADAPT-CHF), designed to

investigate the safety and efficacy of renal denervation in

patients with heart failure, has been initiated.

Sleep apnea

Patients with AF have a high prevalence of OSA [65], and

conversely, a high prevalence of AF ranging from 40 to

Fig. 1 Different mechanisms of atrial fibrillation (AF) in hyperten-

sion, heart failure and sleep apnea, focusing on potential targets of

renal denervation (RDN). Structural and electrical remodeling loops

are shown. Acute atrial stretch, vagal activation and sympathetic

activation during the different pathologies can alter ion current

activation and result in abbreviation of the action potential. In the

structural loop, chronic atrial stretch and the renin–angiotensin–

aldosterone system (RAAS) activates numerous signaling cascades

that produce alterations of the extracellular matrix and conduction

disturbances. Reentrant mechanisms are promoted by both, shortening

of refractoriness (electrical loop) as well as by conduction distur-

bances resulting from tissue fibrosis (structural loop) together creating

a substrate for AF. Sympathetic activation is believed to lead to

changes in calcium handling resulting in spontaneous focal discharges

which can trigger AF. Modulation of sympathetic activation by RDN

may show antiarrhythmic effects by reducing focal discharges

(trigger) and preventing the progression of atrial structural and

electrophysiological changes (substrate) in hypertension, heart failure

and sleep apnea

Clin Res Cardiol

123

50 % has been reported, also in the absence of an under-

lying cardiac disease [66]. The presence of OSA is a strong

predictor for AF and of recurrence of AF after a successful

cardioversion [67, 68]. A meta-analysis revealed a 25 %

higher risk of recurrence of AF following catheter ablation

in OSA patients [69]. Response to antiarrhythmic drugs in

patients with atrial fibrillation is related to the severity of

obstructive sleep apnea [70]. In addition, OSA is associated

with significant atrial remodeling characterized by atrial

enlargement, reduction in voltage, site-specific and wide-

spread conduction abnormalities, and longer sinus node

recovery in humans [21]. Acute atrial dilation together with

changes in blood gasses during obstructive respiratory

events in OSA may alter ion current activation [23]. In a pig

model for OSA, shortening in atrial refractoriness [70]

acutely induced by applied negative thoracic pressure (OSA

maneuver) (Fig. 2) was mainly mediated by combined

sympathovagal activation, since it could be influenced by

atropine, bilateral vagotomy or beta-receptor blockade [47,

71]. Compared to beta-blocker treatment, RDN resulted in

an even more pronounced attenuation of shortening in atrial

refractoriness during OSA maneuvers, which might explain

the superior antiarrhythmic effect of RDN compared to

beta-blocker therapy in this animal model [45] (Fig. 3).

Importantly, clinically used antiarrhythmic drugs such as

amiodarone or sotalol displayed a considerably less pro-

nounced antiarrhythmic effect compared to RDN in the

same pig model for OSA [72]. In pigs with repetitive OSA

maneuvers over 4 h, RDN inhibited spontaneous atrial

premature beats, spontaneous AF episodes as well as AF

duration [73]. RDN attenuated the postapneic blood pres-

sure rises as well as the renin angiotensin system activation,

which may prevent the development of an atrial structural

remodeling process in long-term OSA (Fig. 4) [73]. The

observed reduction in spontaneous atrial extrabeats by RDN

may reduce the trigger for AF in OSA. Furthermore, RDN

has been shown to influence OSA severity by reduction of

hypoxia and occurrence of apnoea in patients with resistant

hypertension [74].

Clinical observations and ongoing trials

In a small study in humans with resistant hypertension, the

atrial antiarrhythmic effects of circumferential pulmonary

vein isolation (PVI) combined with RDN were investigated

[75]. Patients who received both procedures showed signif-

icant reductions in average systolic and diastolic blood

Fig. 2 Changes in atrial effective refractory period (AERP) during

2 min of tracheal occlusion with applied negative tracheal pressure

(NTP) in a pig model for OSA. Below, an individual example of

corresponding monophasic action potential (MAP) signals during

representative AERP measurements at the end of 2 min of tracheal

occlusion is shown. Applied NTP resulted in a progressive shortening

of AERP and MAP, and AF was inducible by a premature beat during

the S1–S2 AERP measurement procedure

Fig. 3 Representative atrial multiple action potential (MAP) record-

ings during AERP measurements before and after RDN or atenolol in

a pig model for OSA. Percent of OSA maneuvers (2 min of tracheal

occlusion with applied negative tracheal pressure) with inducible

atrial fibrillation (AF) and effect of RDN and atenolol

Clin Res Cardiol

123

pressure, whereas those in the PVI-only group did not show

any significant improvement in blood pressure. Other elec-

trophysiological parameters were not obviously changed by

RDN. At 1-year follow-up, 69 % of patients who received

both procedures had no longer AF recurrences, compared to

29 % of those in the PVI-only group [75]. In a case report,

even RDN without PVI reduced blood pressure and attenu-

ated paroxysmal AF episodes, which were symptomatic and

drug-resistant before RDN [76]. The H-FIB study [77] is a

multicenter prospective, double-blind, randomized (1:1)

controlled trial that will test the hypothesis that adjunctive

renal sympathetic denervation, at the time of AF ablation,

will increase the freedom from recurrent AF after PVI in

hypertensive but not in drug-resistant hypertensive patients.

There are at least 11 clinical trials ongoing at the moment

(see clinicaltrials.gov). Most of them are focusing on the

adjuvant role of RDN in combination with PVI vs. PVI only,

but also the effect of RDN alone compared to optimal anti-

arrhythmic drug treatment will be addressed. An overview of

design, sites and time schedule of ongoing trials can be found

in Table 1.

Ventricular arrhythmias and renal denervation

In a pig model with acute myocardial infarction, RDN has

been shown to reduce ventricular ectopics and ventricular

fibrillation after acute myocardial ischemia, while reper-

fusion arrhythmias were not diminished [78]. Furthermore,

a small case series has provided evidence that in patients

with dilated cardiomyopathy and an electrical storm, renal

denervation was able to reduce discharges from the ICDs

and ventricular ectopics [79]. In addition, in a patient after

acute ST-elevation myocardial infarction recurrent mono-

morphic ventricular tachycardia and fibrillation episodes

remained an evident problem despite maximum antiar-

rhythmic drug and initial successful VT ablation. RDN was

performed and ICD interrogation and 24-h Holter moni-

toring excluded recurrent episodes of VT or VF at a

6-month follow-up after the procedure [80].

Conclusions

Despite recent advances, therapy of AF remains a challenge.

AF is characterized by increased sympathetic nerve activity,

changes in atrial sympathetic innervation and structural

remodeling. RDN is a promising strategy to modulate the

autonomic nervous system resulting in reduced sympathetic

activity. Modulation of sympathetic tone by RDN may pre-

vent progression of AF and improve PVI outcome by direct

atrial electrophysiological effects as well as by antiremod-

eling effects, particularly in the state of increased sympa-

thetic drive such as hypertension, sleep apnea and heart

failure. In addition, early results also suggest promising

antiarrhythmic effects by RDN in the ventricle. Randomized

placebo-controlled studies are needed to show whether

sympathetic inhibition by RDN exerts antiarrhythmic effects

and improves ablation outcome independent of blood

pressure.

Fig. 4 Blood pressure during

repetitive OSA maneuvers:

a blood pressure registration in

control (Ctr) pigs, b pigs with

repetitive obstructive

respiratory events with applied

negative tracheal pressure

(NTP) without and c with RDN

(NTP ? RDN). RAAS-

signaling components d, e effect

of 4 h of repetitive OSA

maneuvers on d plasma renin

activity and e plasma

aldosterone concentrations

Clin Res Cardiol

123

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Clin Res Cardiol

123

Conflict of interest MB, HRN, SHS, CU are supported by the

Deutsche Forschungsgemeinschaft (KFO 196). DL and FM are sup-

ported by the Deutsche Hochdruckliga (DHL) and MB and FM by the

Deutsche Gesellschaft fur Kardiologie (DGK). The authors received

scientific support from Medtronic, St. Jude, Covidien and Cordis.

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