Shaojie Chen ORCID iD: 0000-0002-7082-9573

Synergy of pulmonary vein isolation and catheter renal

denervation in atrial fibrillation complicated with

uncontrolled hypertension: mapping the renal

Accepted Article

sympathetic nerve and pulmonary vein (the PVI plus

RDN strategy)?

Shaojie Chen, MD, PhD1, Marcio G. Kiuchi, MD, PhD2, Yuehui Yin, MD3,

Shaowen Liu, MD, PhD4, Alexandra Schratter, MD5, Willem-Jan Acou, MD6,

Christian Meyer, MD7, Helmut Pürerfellner, MD8, K. R. Julian Chun, MD1, Boris

Schmidt, MD1

1. Frankfurt Academy For Arrhythmias (FAFA), Cardioangiologisches Centrum

Bethanien (CCB) Frankfurt am Main, Medizinische Klinik III, Agaplesion
Markus Krankenhaus, Frankfurt am Main, Germany.

2. School of Medicine-Royal Perth Hospital Unit, University of Western

Australia.

3. Department of Cardiology, The Second Affiliated Hospital of Chongqing

Medical University, Chongqing Cardiac Arrhythmia Service Center,
Chongqing, China.

This article has been accepted for publication and undergone full peer review but
has not been through the copyediting, typesetting, pagination and proofreading
process, which may lead to differences between this version and the Version of
Record. Please cite this article as doi: 10.1111/jce.13858.

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 4. Department of Cardiology, Shanghai First People’s Hospital / Shanghai
General Hospital, Shanghai Jiao Tong University School of Medicine,
Shanghai, China.

5. Medizinische Abteilung mit Kardiologie, Krankenhaus Hietzing Wien, Vienna,

Austria.
Accepted Article
6. Department of Cardiology, AZ Delta, Roeselare, Belgium.

7. Klinik für Kardiologie mit Schwerpunkt Elektrophysiologie, Universitäres

Herzzentrum Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg;
DZHK (German Centre for Cardiovascular Research), Partner Site
Hamburg/Kiel/Lübeck, Germany.

8. Abteilung der kardialen Elektrophysiologie/Kardiologie, Akademisches

Lehrkrankenhaus der Elisabethinen, Ordensklinikum Linz Elisabethinen, Linz,
Austria.

Conflict of interest: The authors declare no conflicts of interest regarding the

content of the study.

*Correspondence to: Frankfurt Academy For Arrhythmias (FAFA), The

Cardioangiologisches Centrum Bethanien (CCB) Frankfurt am Main,

Medizinische Klinik III, Agaplesion Markus Krankenhaus, Wilhelm-Epstein

Straße 4, Frankfurt am Main, 60431, Germany.

Tel: +49-069-945028-131; Fax: +49 69-945028-119; Email:

drsjchen@126.com;sj.chen@gmx.de; j.chun@ccb.de; b.schmidt@ccb.de;

Introduction: Disturbance of sympathetic and vagal nervous system participates

in the pathogenesis of hypertension and atrial fibrillation (AF). Renal denervation

(RDN) can modulate autonomic nervous activity and reduce blood pressure (BP)

This article is protected by copyright. All rights reserved.

 in hypertensive patients. We aimed to evaluate the effect of RDN combined with

pulmonary vein isolation (PVI) in patients with AF and hypertension.

Methods and Results: Clinical trials including randomized data comparing PVI
Accepted Article
plus RDN versus PVI alone were enrolled. Primary outcome was incidence of AF

recurrence after procedure.

A total of 387 patients, of them 252 were randomized, were enrolled. Mean age

was 57±10 years, 71% were male, and mean left ventricular ejection fraction was

57.4±6.9%. Follow-up for randomized data was 12 months. Overall comparison

for primary outcome showed that PVI plus RDN was associated with significantly

lower AF recurrence as compared with PVI alone (35.8% vs. 55.4%, P<0.0001).

This advantageous effect was consistently maintained among randomized patients

(37.3% vs. 61.9%, OR: 0.37, P=0.0001), and among patients with implanted

devices for detection of AF recurrence (38.9% vs. 61.6%, P=0.007). Post-hoc

sensitivity and regression analysis demonstrated very good stability of this

primary result. Pooled Kaplan-Meier analysis further showed that PVI plus RDN

was associated with significantly higher freedom from AF recurrence as compared

with PVI alone (Log-rank test, P=0.001). Besides, RDN resulted in significant BP

reduction without additionally increasing the risk of adverse events.

This article is protected by copyright. All rights reserved.

 Conclusions: RDN may provide synergetic effects with PVI to reduce the burden

of AF and improve BP control in patients with AF and uncontrolled hypertension.

Key words: atrial fibrillation, ablation, pulmonary vein isolation, autonomic

Accepted Article
nerve, renal denervation, blood pressure, hypertension

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and hypertension

is the most prevalent risk factor for the development AF. Both diseases are

significantly associated with increased morbidity and mortality and exert adverse

impact on patients’ quality of life. Despite optimal antihypertensive

pharmacotherapy, a large portion of hypertensive patients may have their blood

pressure (BP) unsatisfactorily controlled [1]. AF patients complicated with

uncontrolled hypertension are predicted to be associated with even worse clinical

prognosis [2].

Pulmonary isolation (PVI) has been established as the cornerstone ablation

strategy regardless of the patterns of AF [3,4]. For patients with uncontrolled

hypertension, catheter based renal denervation (RDN) has been introduced to

improve BP control by modulating the sympathetic nervous system [5-9].

Pathophysiological, disturbance of the sympathetic and vagal nervous system

contribute a crucial role in the pathogenesis of both hypertension and AF [10]. The

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 present study aimed at evaluating the adjunctive effect of RDN combined with

PVI to treat AF by conducting a pooled analysis.

Methods
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The study was a pooled analysis, and the protocol was reviewed by the institution

review board. We performed study search via the PubMed, The Cochrane Library

and Clinicaltrial.gov database until November 2018, using the keywords: atrial

fibrillation, renal denervation.

The inclusion criteria were: 1). Patients with atrial fibrillation, 2). Comparative

clinical studies, 3) Intervention: pulmonary vein isolation plus renal denervation

(PVI+RDN) compared with PVI alone, 3) end-point: rate of AF recurrence. Data

with respect to study character, demographic characteristics, echocardiography

measure, intervention, and follow-up were extracted and collected.

The primary outcome was incidence of AF recurrence which was defined as >30s

documented AF (including left atrial tachycardia/flutter) after a single ablation

procedure off antiarrhythmic drugs (AADs). The first 3 months as blanking period

was excluded from the analysis. We also assessed the changes of BP after the

procedure. Follow-up visits were scheduled at 3, 6, 9, 12 months. AF recurrence

was based on either Holter monitoring or implanted devices (implantable cardiac

monitor or pacemaker).

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 Statistical analysis

The categorical variables were presented as percentages and estimated by odds

ratio (ORs). Continuous variables were described as mean and standard deviation
Accepted Article
(SD) and analyzed by weighted mean difference (WMD). Statistic value I2

assessed by Q test was used to quantify the degree of inter-study heterogeneity.

Given the intrinsic heterogeneity between studies, we calculated the OR and

WMD estimates using random-effects models for all assessment. All P values

were two-tailed with 95% confidence interval (CI), and the statistical significance

was set at 0.05. Statistical analyses were performed using the SPSS package (17.0,

Chicago, IL) and Revman (5.3, the Cochrane Collaboration, Copenhagen).

Results

Demographic results

The initial search generated ninety citations. After screening titles and abstracts,

twenty-nine citations were excluded. Sixty-one full-texts were assessed, of them

fifty-six were excluded (including 36 reviews, 2 case reports, 2 study designs, 16

experimental studies). Consequently, five comparative clinical trials were included.

Table 1 shows the characters of study design. Table 2 summarizes the patients’

baseline characteristics of the individual studies. Table 3 presents the pooled

baseline demographic features of the included patients.

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 Overall 387 symptomatic, AADs refractory AF patients with hypertension were

enrolled, mean age was 57±10 years, and male patients were 71%. Mean left

atrial diameter (LAD) was 44±8mm, mean left ventricular ejection fraction

(LVEF) was 57.4±6.9%. Four out of five trials were randomized controlled trial
Accepted Article

(RCT) with “double-blinded” design. Ablation strategy for AF was 3 dimensional

mapping systems (CARTO, Biosense-Webster, Diamond Bar, CA; or EnSite

Velocity, St. Jude Medical, St. Paul, MN) guided PVI only without additionally

linear ablation. The approach for RDN was bilateral, full-length renal artery

ablation using irrigated catheter or Simplicity system (Medtronic, Minneapolis,

MN) or EnligHTN system (St. Jude Medical, St. Paul, MN) with 8-12 Watts 1-2

min for each application, aiming at 4-8 lesions each side. The follow-up for RCTs

was 12 months.

Primary outcomes

Figure 1-A shows the pooled analysis for overall comparison. A total of 387

patients were included, PVI+RDN group was associated with significantly lower

AF recurrence as compared with PVI alone group (35.8% vs. 55.4%, OR: 0.4,

95%CI: 0.26-0.62, I2: 0%, P<0.0001).

Figure 1-B shows the pooled analysis of RCTs, a total of 252 AF patients were

included in this subset, patients randomized to receive PVI+RDN were found to

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 have significantly less AF recurrence as compared to those randomized to PVI

alone (37.3% vs. 61.9%, OR: 0.37, 95%CI: 0.22-0.62, I2: 0%, P=0.0001).

Figure 1-C shows the pooled analysis of RCTs using implanted cardiac device for
Accepted Article
detection of AF recurrence. A total of 145 patients were included in this subset,

consistently, patients randomized to receive PVI+RDN were found to have

significantly less AF recurrence as compared to those randomized to PVI alone

(38.9% vs. 61.6%, OR: 0.40, 95%CI: 0.20-0.78, I2= 0%, P=0.007).

The sensitivity analysis further using “one-trial moving out” technique

demonstrated very good stability of the primary outcome favoring PVI plus RDN

over PVI alone (Figure 2).

Kaplan-Meier analysis

Figure 3 presents the pooled Kaplan-Meier curves for freedom from AF

recurrence detected by implanted cardiac devices. During a 12 months’ follow-up

after ablation procedure, PVI+RDN was shown to be associated significantly

higher freedom from AF recurrence as compared with PVI alone (61.1% vs.

38.4%, Log-rank test, P=0.001).

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 Multi-variables regression analysis

Table 4 shows the result of meta-regression analysis based on known variables

against recurrence of AF. Clinical characteristics including age, gender,

Accepted Article
patterns/history of AF, comorbidities, body mass index (BMI), left atrial diameter

(LAD), LVEF (left ventricular ejection fraction), estimated glomerular filtration

rate (eGFR), and (antiarrhythmic drugs) AADs were not found to significantly

impact the recurrence of AF in this pooled study.

Effect of RDN on BP and safety events

Table 5 summarizes the pooled effect of RDN on BP. During the 12 months

follow-up, RDN was shown to significantly reduce the office systolic BP (-21±7

mm Hg) and office diastolic BP (-10±2.7 mm Hg), as well as mean systolic BP

(-8±2.6mm Hg) and mean diastolic BP (-8.6±3 mmHg) (all P<0.05 for before-after

comparison and between RDN vs. non-RDN group comparison). As summarized

in Table 5, no procedure-related adverse events were observed.

Discussion

RDN to treat hypertension

Hypertension presents a major health problem worldwide and it is associated with

significantly increased risk of cardiovascular adverse events [1,11]. Although

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 pharmacological therapy for hypertension is well accepted, a large proportion of

hypertensive patients fail to achieve target BP due to non-adherence or side effects

despite maximal tolerated regimens [12]. Thus a non-pharmacotherapy for

patients with uncontrolled hypertension appears rationale. Renal sympathetic

Accepted Article

nervous activity represents a pivotal neurogenic mechanism in hypertension. The

concept of RDN as a catheter-based treatment technique aiming at better BP

control by modulating sympathetic nervous activity has been proposed and

intensively researched [13-22].

Since the first description of the novel technique [23], numerous studies including

randomized and observational trials have demonstrated that catheter-based RDN

resulted in substantial reduction in BP in patients with resistant hypertension [24].

Most recently, three multicenter, randomized, sham-controlled studies using new

generation of RDN device continue to show cogent evidence of significant BP

reduction in patients with uncontrolled hypertension [7-9].

Catheter ablation for AF

On the other hand AF is the most common arrhythmia and its prevalence is

expected to surge in the aging population of the world in the upcoming years.

Besides clinical symptoms, AF is associated with serious morbidity and increased

mortality [3]. The efficacy of current AADs in AF is very disappointing with

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 around 30% success rate to restore sinus rhythm. Established catheter ablation

strategy for AF namely PVI is based on the knowledge that arrhythmogenic foci

arising from the pulmonary vein sleeve can trigger and perpetuate AF. Though

associated with alleviated symptoms, improved quality of life and even survival
Accepted Article

benefit [25], the success rate of catheter ablation reported in existing AF ablation

trials ranges from 50-80% after one or more ablation procedures, and this rate

becomes even frustrating when ablating persistent or long-standing AF [26-28].

The gap of the ablation success suggests that additional mechanisms such as

up-stream risk factors, non-PV triggers, substrate/electrical remodeling,

disturbance of autonomic nerves may play important role in the progress of AF

[29,30].

In our pooled data analysis, the one-year success rate in the PVI alone group was

only approximate 40% versus 62% in the PVI plus RND group, and this outcome

was consistent with the pooled analysis of randomized patient data and in patients

with implanted device. It should be noted, one major demographic difference

between our study and the existing AF ablation trials is the uncontrolled

hypertension [SBP 160 mmHg (140mmHg-180mmHg)] among our study patients.

As it is known that increased BP is one of the most important risk factors for the

development of AF, the low success rate in the PVI alone group may be very

likely attributed to the uncontrolled increased BP, whereas patients with controlled

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 BP in the RDN plus PVI group was associated with substantially higher freedom

from arrhythmia recurrence as compared to the former. To this extent, our study

echoes the importance of the upstream risk factors management (i.e. better BP

control) for the reduction of AF incidence.

Accepted Article

Adjunctive role of RDN in AF—experimental investigations

Hypertension is a common, modifiable risk factor in patients with AF. Adequate

control of BP reduces stroke risk, bleeding risk on anticoagulation, and attenuates

the adverse outcomes of AF [3]. Pathophysiologically, imbalance of the

sympathetic and vagal nervous system participates in the pathogenesis of both

diseases [10]. Therapeutic approach to modulate sympathetic tone appears

plausible as a “one stone two birds” strategy. A number of experimental studies

investigated the mechanism underlying the potential antiarrhythmic effects of

RDN. As summarized in Table 6, these basic studies demonstrated that, beyond

BP reduction, RDN can prevent atrial electrophysiological changes, reverse atrial

electrical and structural remodeling further reduce AF inducibility and AF

episodes via modulating renal sympathetic nervous activity [31-44]. The favorable

antiarrhythmic effects independent of BP lowering were also observed at human

research level [45]. Collectively, these mechanism investigations provide in-depth

and rational explanations for the positive clinical outcome of the present study.

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 Ablation technique considerations

While PVI has been well recognized as an established ablation approach with

clear endpoint using either radiofrequency or cryo-energy in treating AF [46-47],

Accepted Article
RDN currently on the other hand remains at a stage of “blinded ablation” [48].

Several factors such as patient selection, baseline BP patterns, antihypertensive

medications, comorbidities, ablation devices and acute BP response have been

reported to be related to the response of RDN [19, 49, 50]. At technique level,

electrical stimulation at intraluminal renal artery using electrical catheter aiming at

inducing BP elevation measured before and after the ablation procedure has been

used to assess the extent of denervation [51-55]. The stimulation technique may

be used as a practical approach to map the renal autonomic nerves adjacent to

renal artery and as a guidance to perform “selective renal sympathetic nerve

ablation”.

With respect to the vascular ablation lesions induced by RDN, a previous study

enrolled patients with treatment-resistant hypertension for RDN using different

devices; in this study optical coherence tomography at renal arteries was

performed before and after RDN. The investigators found diffuse renal artery

constriction and local tissue damage at the ablation site with edema and thrombus

formation occurred after RDN, suggesting that antiplatelet therapy may be

required during RDN [56].

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 Significance of the present study and on-going studies

In the present study five clinical trials charactering 387 patients with AF and

hypertension were included. The study demonstrated that PVI combined with
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RDN is associated with significantly lower AF recurrence and better BP control as

compared with PVI alone. Notably, the patients' inclusion in individual studies

was consistent, and all procedures were performed in experienced centers for PVI

and RDN using similar ablation strategy. The statistical analysis showed a very

good inter-study homogeneity during the data combination, and the primary

outcome is well maintained in randomized subset and in sensitivity analysis.

Particularly, two RCTs employed implanted devices (loop recorder and pacemaker)

for the detection of AF recurrence, and the pooled Kaplan-Meier analysis

demonstrated very consistent results favoring PVI plus RDN over PVI alone.

During the study period no procedure-related adverse events were observed and

the safety profile of the procedure was well exhibited and in line with existing

consensus [57].

On the basis of the promising results of the RDN in treating resistant hypertension

and its potential role in management of cardiac arrhythmias, a number of

registered clinical trials are ongoing to investigate the adjunctive effect of RDN on

AF [58]. Of note, the most recent ASAF trial (Ablation of Sympathetic Atrial

Fibrillation) is a multicenter randomized controlled study aiming to investigate

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 whether RDN added to PVI reduces AF recurrence. The study will enroll AF

patients with uncontrolled hypertension and signs of sympathetic overdrive, and

the renal nerve stimulation technique will be used in the procedure to assess the

physical response of RDN [59].

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Limitations

Several limitations should be mentioned when interpreting the results. Though the

effects of RDN on AF have been extensively investigated in preclinical researches,

the clinical application combining PVI with RDN to treat AF and hypertension

remains at a “proof-of-concept” level, thus the patient enrollment has to be very

careful and the number of patients included in the study is indeed limited.

However, prospective, randomized and double-blinded data were enrolled and

combined, enhancing the rigorousness of the statistical results. The follow-up

period was only 12 months, thus long-term efficacy of the studied intervention

cannot be extrapolated.

Conclusions

This study suggests that PVI combined with RDN can be a feasible, safe,

interventional therapy option for patients with AF and uncontrolled hypertension.

RDN may improve BP control and provide synergetic beneficial effects to reduce

This article is protected by copyright. All rights reserved.

 the burden of AF when collaborated with PVI. These promising results should be

validated in larger, multicenter, randomized trials.

Acknowledgements: We thank all the participants in this study for the scientific
Accepted Article
contribution.

Conflict of interest: None declared.

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cardiac ablation catheter on blood pressure and renal function in patients with

chronic kidney disease and resistant hypertension. Eur Heart J. 2013

Jul;34(28):2114-21.

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 23. Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal

sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med. 2009

Aug 27;361(9):932-4.
Accepted Article
24. Davis MI, Filion KB, Zhang D, Eisenberg MJ, Afilalo J, Schiffrin EL, Joyal D.

Effectiveness of renal denervation therapy for resistant hypertension: a systematic

review and meta-analysis. J Am Coll Cardiol. 2013 Jul 16;62(3):231-241.

25. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L,

Merkely B, Pokushalov E, Sanders P, Proff J, Schunkert H, Christ H, Vogt J,

Bänsch D; CASTLE-AF Investigators. Catheter Ablation for Atrial Fibrillation

with Heart Failure. N Engl J Med. 2018 Feb 1;378(5):417-427. doi:

10.1056/NEJMoa1707855.

26. Ouyang F, Tilz R, Chun J, Schmidt B, Wissner E, Zerm T, Neven K, Köktürk

B, Konstantinidou M, Metzner A, Fuernkranz A, Kuck KH. Long-term results of

catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up.

Circulation. 2010 Dec 7;122(23):2368-77.

27. Schreiber D, Rostock T, Fröhlich M, Sultan A, Servatius H, Hoffmann BA,

Lüker J, Berner I, Schäffer B, Wegscheider K, Lezius S, Willems S, Steven D.

Five-year follow-up after catheter ablation of persistent atrial fibrillation using the

This article is protected by copyright. All rights reserved.

 stepwise approach and prognostic factors for success. Circ Arrhythm

Electrophysiol. 2015 Apr;8(2):308-17.

28. Tilz RR, Rillig A, Thum AM, Arya A, Wohlmuth P, Metzner A, Mathew S,
Accepted Article
Yoshiga Y, Wissner E, Kuck KH, Ouyang F. Catheter ablation of long-standing

persistent atrial fibrillation: 5-year outcomes of the Hamburg Sequential Ablation

Strategy. J Am Coll Cardiol. 2012 Nov 6;60(19):1921-9.

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28;120(9):1501-1517.

31. Linz D, Mahfoud F, Schotten U, Ukena C, Neuberger HR, Wirth K, Böhm M.

Renal sympathetic denervation suppresses postapneic blood pressure rises and

atrial fibrillation in a model for sleep apnea. Hypertension. 2012 Jul;60(1):172-8.

32. Zhao Q, Yu S, Zou M, Dai Z, Wang X, Xiao J, Huang C. Effect of renal

sympathetic denervation on the inducibility of atrial fibrillation during rapid atrial

pacing. J Interv Card Electrophysiol. 2012 Nov;35(2):119-25.

This article is protected by copyright. All rights reserved.

 33. Zhao Q, Yu S, Huang H, Tang Y, Xiao J, Dai Z, Wang X, Huang C. Effects of

renal sympathetic denervation on the development of atrial fibrillation substrates

in dogs with pacing-induced heart failure. Int J Cardiol. 2013 Sep

30;168(2):1672-3.
Accepted Article

34. Linz D, Mahfoud F, Schotten U, Ukena C, Neuberger HR, Wirth K, Böhm M.

Effects of electrical stimulation of carotid baroreflex and renal denervation on

atrial electrophysiology. J Cardiovasc Electrophysiol. 2013 Sep;24(9):1028-33.

35. Wang X, Zhao Q, Huang H, Tang Y, Xiao J, Dai Z, Yu S, Huang C. Effect of

renal sympathetic denervation on atrial substrate remodeling in ambulatory

canines with prolonged atrial pacing. PLoS One. 2013 May 27;8(5):e64611.

36. Hou Y, Hu J, Po SS, Wang H, Zhang L, Zhang F, Wang K, Zhou Q.

Catheter-based renal sympathetic denervation significantly inhibits atrial

fibrillation induced by electrical stimulation of the left stellate ganglion and rapid

atrial pacing. PLoS One. 2013 Nov 6;8(11):e78218.

37. Wang X1, Zhao Q, Deng H, Wang X, Guo Z, Dai Z, Xiao J, Wan P, Huang C.

Effects of renal sympathetic denervation on the atrial electrophysiology in dogs

with pacing-induced heart failure. Pacing Clin Electrophysiol. 2014

Oct;37(10):1357-66.

This article is protected by copyright. All rights reserved.

 38. Wang X, Huang C, Zhao Q, Huang H, Tang Y, Dai Z, Wang X, Guo Z, Xiao J.

Effect of renal sympathetic denervation on the progression of paroxysmal atrial

fibrillation in canines with long-term intermittent atrial pacing. Europace. 2015

Apr;17(4):647-54.
Accepted Article

39. Linz D, van Hunnik A, Hohl M, Mahfoud F, Wolf M, Neuberger HR, Casadei

B, Reilly SN, Verheule S, Böhm M, Schotten U. Catheter-based renal denervation

reduces atrial nerve sprouting and complexity of atrial fibrillation in goats. Circ

Arrhythm Electrophysiol. 2015 Apr;8(2):466-74.

40. Liang Z, Shi XM, Liu LF, Chen XP, Shan ZL, Lin K, Li J, Chen FK, Li YG,

Guo HY, Wang YT. Renal denervation suppresses atrial fibrillation in a model of

renal impairment. PLoS One. 2015 Apr 17;10(4):e0124123.

41. Zhou Q, Zhou X, TuEr-Hong ZL, Wang H, Yin T, Li Y, Zhang L, Lu Y, Xing

Q, Zhang J, Yang Y, Tang B. Renal sympathetic denervation suppresses atrial

fibrillation induced by acute atrial ischemia/infarction through inhibition of

cardiac sympathetic activity. Int J Cardiol. 2016 Jan 15;203:187-95.

42. Wei Y, Xu J, Zhou G, Chen S, Ouyang P, Liu S. Renal Denervation Suppresses

the Inducibility of Atrial Fibrillation in a Rabbit Model for Atrial Fibrosis. PLoS

One. 2016 Aug 16;11(8):e0160634.

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 43. Yamada S, Lo LW, Chou YH, Lin WL, Chang SL, Lin YJ, Chen SA. Renal

denervation regulates the atrial arrhythmogenic substrates through reverse

structural remodeling in heart failure rabbit model. Int J Cardiol. 2017 May

15;235:105-113.
Accepted Article

44. Yamada S, Fong MC, Hsiao YW, Chang SL, Tsai YN, Lo LW, Chao TF, Lin

YJ, Hu YF, Chung FP, Liao JN, Chang YT, Li HY, Higa S, Chen SA. Impact of

Renal Denervation on Atrial Arrhythmogenic Substrate in Ischemic Model of

Heart Failure. J Am Heart Assoc. 2018 Jan 22;7(2). pii: e007312.

45. McLellan AJ, Schlaich MP, Taylor AJ, Prabhu S, Hering D, Hammond L,

Marusic P, Duval J, Sata Y, Ellims A, Esler M, Peter K, Shaw J, Walton A,

Kalman JM, Kistler PM. Reverse cardiac remodeling after renal denervation:

Atrial electrophysiologic and structural changes associated with blood pressure

lowering. Heart Rhythm. 2015 May;12(5):982-90.

46. Kuck KH, Brugada J, Fürnkranz A, Metzner A, Ouyang F, Chun KR, Elvan A,

Arentz T, Bestehorn K, Pocock SJ, Albenque JP, Tondo C; FIRE AND ICE

Investigators. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial

Fibrillation. N Engl J Med. 2016 Jun 9;374(23):2235-45.

This article is protected by copyright. All rights reserved.

 47. Chen S, Schmidt B, Bordignon S, Bologna F, Perrotta L, Nagase T, Chun KRJ.

Atrial fibrillation ablation using cryoballoon technology: Recent advances and

practical techniques. J Cardiovasc Electrophysiol. 2018 Jun;29(6):932-943.

Accepted Article
48. Esler M, Guo L. The future of renal denervation. Auton Neurosci. 2017

May;204:131-138.

49. Barber-Chamoux N, Esler MD. Predictive factors for successful renal

denervation: should we use them in clinical trials? Eur J Clin Invest. 2017

Nov;47(11):860-867.

50. Xu Y, Xiao P, Fan J, Chen W, Du H, Ling Z, Liu Z, Su L, Woo K, Yin Y. Blood

pressure elevation response to radiofrequency energy delivery: one novel

predictive marker to long-term success of renal denervation. J Hypertens. 2018 Jul

11. doi: 10.1097/HJH.0000000000001839. [Epub ahead of print]

51. Chinushi M, Izumi D, Iijima K, Suzuki K, Furushima H, Saitoh O, Furuta Y,

Aizawa Y, Iwafuchi M. Blood pressure and autonomic responses to electrical

stimulation of the renal arterial nerves before and after ablation of the renal artery.

Hypertension. 2013 Feb;61(2):450-6.

52. Lu J, Wang Z, Zhou T, Chen S, Chen W, Du H, Tan Z, Yang H, Hu X, Liu C,

Ling Z, Liu Z, Zrenner B, Woo K, Yin Y. Selective proximal renal denervation

guided by autonomic responses evoked via high-frequency stimulation in a

This article is protected by copyright. All rights reserved.

 preclinical canine model. Circ Cardiovasc Interv. 2015 Jun;8(6). pii: e001847. doi:

10.1161/CIRCINTERVENTIONS.115.001847.

53. de Jong MR, Adiyaman A, Gal P, Smit JJ, Delnoy PP, Heeg JE, van Hasselt
Accepted Article
BA, Lau EO, Persu A, Staessen JA, Ramdat Misier AR, Steinberg JS, Elvan A.

Renal Nerve Stimulation-Induced Blood Pressure Changes Predict Ambulatory

Blood Pressure Response After Renal Denervation. Hypertension. 2016

Sep;68(3):707-14.

54. de Jong MR, Hoogerwaard AF, Adiyaman A, Smit JJJ, Heeg JE, van Hasselt

BAAM, Misier ARR, Elvan A. Renal nerve stimulation identifies aorticorenal

innervation and prevents inadvertent ablation of vagal nerves during renal

denervation. Blood Press. 2018 Oct;27(5):271-279.

55. Tsioufis KP, Feyz L, Dimitriadis K, Konstantinidis D, Tousoulis D, Voskuil M,

Mahfoud F, Daemen J. Safety and performance of diagnostic electrical mapping of

renal nerves in hypertensive patients. EuroIntervention. 2018 Sep 18. pii:

EIJ-D-18-00536. doi: 10.4244/EIJ-D-18-00536. [Epub ahead of print]

56. Templin C, Jaguszewski M, Ghadri JR, Sudano I, Gaehwiler R, Hellermann JP,

Schoenenberger-Berzins R, Landmesser U, Erne P, Noll G, Lüscher TF. Vascular

lesions induced by renal nerve ablation as assessed by optical coherence

tomography: pre- and post-procedural comparison with the Simplicity catheter

This article is protected by copyright. All rights reserved.

 system and the EnligHTN multi-electrode renal denervation catheter. Eur Heart J.

2013 Jul;34(28):2141-8.

57. Schmieder RE, Mahfoud F, Azizi M, Pathak A, Dimitriadis K, Kroon AA, Ott
Accepted Article
C, Scalise F, Mancia G, Tsioufis C; Members of the ESH Working Group on

Interventional Treatment of Hypertension. European Society of Hypertension

position paper on renal denervation 2018. J Hypertens. 2018

Oct;36(10):2042-2048.

58. Kosiuk J, Hilbert S, Pokushalov E, Hindricks G, Steinberg JS, Bollmann A.

Renal denervation for treatment of cardiac arrhythmias: state of the art and future

directions. J Cardiovasc Electrophysiol. 2015 Feb;26(2):233-8.

59. de Jong MR, Hoogerwaard AF, Adiyaman A1, Smit JJJ, Ramdat Misier AR,

Heeg JE, van Hasselt BAAM, Van Gelder IC, Crijns HJGM, Lozano IF6, Toquero

Ramos JE, Javier Alzueta F, Ibañez B, Rubio JM, Arribas F, Porres Aracama JM,

Brugada J, Mont L, Elvan A. Treatment of atrial fibrillation in patients with

enhanced sympathetic tone by pulmonary vein isolation or pulmonary vein

isolation and renal artery denervation: clinical background and study design : The

ASAF trial: ablation of sympathetic atrial fibrillation. Clin Res Cardiol. 2018

Jul;107(7):539-547.

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 Figures

Figure 1 Comparison between PVI plus RDN vs. PVI for AF recurrence
Accepted Article

Figure 2 Sensitivity analysis

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 Figure 3 Kaplan-Meier analysis for freedom from AF recurrence
Accepted Article

This article is protected by copyright. All rights reserved.

 Table 1 Study design characters

Strat Metho
egy Strateg Foll d of
Stud Desig Inclusion RDN RDN
of AF y of ow AF
y n criteria catheter points
ablat RDN up follow
Accepted Article
ion up

1.Sympto 1. 3-D 1.Irrigate

matic renal d
drug-refr artery catheter
actory AF mappin
(Paroxys g,
mal or
2.
persistent
Renal
),
artery
2.resistan
stimula Up to
t
JAC tion, 6 12
hypertens 24-h
C RCT PVI points mon
ion 3. Holter
2012 each-si ths
(systolic Bilater de
blood al full
pressure length
≥160 RDN
mm
Hg)*, 4. 8-10
3.GFR≥ Watts,
45 1-2
ml/min/1. Min
2
73 m each

Hear 1.Sympto 1. 3-D 1.Irrigate Up to 12

24-h
t RCT matic PVI renal d 6 mon
Rhyt drug-refr artery catheter, Holter
points ths
hm actory AF mappin 2.Sympli each-si

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 2014 (Paroxys g, city de
mal or system
2.
persistent
Renal
),
artery
2.resistan
stimula
t
tion,
hypertens
Accepted Article

ion 3.
(systolic Bilater
blood al, full
pressure length
≥140 RDN,
mm
Hg)*, 4. 8-12
3.GFR≥ Watts,
45 1-2
ml/min/1. Min
73 m2 each

1. 1. 3-D 1.irrigate
Documen renal d
ted artery catheter,
symptom mappin
atic g,
drug-refr
2.
actory 4-5
Bilater 22
JICE Non- PAF, 2. points 24-h
PVI al, full mon
2016 RCT ABPM each-si Holter
length ths
between de
RDN,
100-130
mmHg, 3.10
3. Watts,
GFR>15 1 Min
mL/min/1 each
.73 m2

This article is protected by copyright. All rights reserved.

 1.Sympto 1. 3-D 1.Irrigate
matic renal d
drug-refr artery catheter,
actory AF mappin 2.Sympli
(Paroxys g, city
mal or system
Accepted Article
2.
persistent
Renal
),
artery
2.resistan
stimula
t
Card tion, Up to
hypertens
io 6 12 ICM
ion 3.
Ther RCT PVI points mon docum
(systolic Bilater
a each-si ths ent
blood al full
2017 de
pressure length
≥ RDN
140mm
Hg or ≥ 4. 8-10
160 mm Watts,
Hg)*, 1-2
3.GFR≥ Min
45 each
ml/min/1.
73 m2

1. 1. 3-D 1.EnligH
Documen renal TN™
At
ted artery
least 8 Pacem
symptom mappin 12
JICE applica aker
RCT atic PVI g, mon
2018 tion docum
drug-refr ths
2. each-si ent
actory
Bilater de
PAF, 2.
al, full
resistant
length
hypertens

This article is protected by copyright. All rights reserved.

 ion RDN,
(ABPMs)
3.8
≥130
Watts,
mmHg*,
1 Min
3.
each
GFR>60
mL/min/1
Accepted Article

.73 m2

* systolic blood pressure≥160 mm Hg despite treatment with ≥3

antihypertensive drugs (including 1 diuretic), ICM: Implantable cardiac monitor

RDN: renal denervation; RCT: randomized controlled trial; AF: atrial fibrillation;
ABPM: ambulant blood pressure monitoring; GFR: glomerular filtration rate; PVI:
pulmonary vein isolation; ICM: implanted cardiac monitor

Table 2 Patients’ baseline characteristics of the individual studies

Hi
sto AA
Ba
M ry Ba Ba Ba Ba Ds
Di seli
St Sam ea M PAF of C B seli seli seli seli aft
ab ne
ud ple n al /Per A A M ne ne ne ne er
ete A
y size a e sAF F D I LA LV SB eG bla
s A
ge (ye D EF P FR nki
Ds
ar ng
s)

PVI: 5 2 2 17 80.
JA 1 5.3 2 50 66 3.6
14 6 (1 8 8 2
C 0 5/9 ± (14 ± ± (2-
± 4 ± ± ±
C 3.2 %) 6 4 5) No
PVI+ 9 % 5 8 4.6
20 1 4/9
RDN )
1 5.7 1 49 65 3.8
12 5 2 18 78
:13 ± (8 ± ± (2-
7 2 8 1 ±

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 ± 4.9 %) (1 ± 7 5 ± 6.1 5)
8 5 6 7
%
)

4
Accepted Article
5 (1 16
77
He 6 3.7 4 0 47 61 4 3.4
PVI: ±
art ± 2 18/2 ± (10 % ± ± ± ±
39 8.5
Rh 6 4 1 2.1 %) ) 4 5 17 1.1
yth PVI+ / No
75.
m RDN 5 3 17/2 4.2 5 5 47 60 16 3.4
5
20 6 1 4 ± (12 (1 ± ± 3 ±
: 41 ±
14 ± 2.5 %) 2 5 4 ± 1.1
9.2
6 % 18
)

5
9 2 11
± 36 7 9 50
PVI:
1 6 (38 ± >5 ± ±
JI 96
5 5 96/0 %) 6 0 8 5.4
CE
/ / / / No
20 PVI+
6 2 39/0 14 2 >5 12 48
16 RDN
0 4 (36 5 0 1 ±
: 39
± %) ± ± 6.8
1 4 9
4

PVI: 5 4 16
Ca 3.7 3 47 61 77 3.4
2 16/2
37 6 (1 4
rdi ± (8 ± ± ± ±
6 1
± 0 ±
o 2 %) / 5 4 8.3 1.2 No
PVI+ 5 % 16
Th 2 15/2
RDN )
era 9 4 4.1 4 47 60 76 3.4
: 39 5 16
20 ± (10 ± ± ± ±
6 4 3

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 17 ± 2.6 %) (1 6 4 ± 9.1 1.2
6 0 20
%
)

9
Accepted Article
5 (2 2 14
8 10 5 6 34 61 0 67 3.7
PVI:
± 3 (28 % ± ± ± ± ± ±
JI 36
5 0 36/0 %) ) 2 7 6 6 7.7 0.4
CE
/ No
20 PVI+
5 2 33/0 8 5 2 37 62 14 69 3.5
18 RDN
7 5 (24 (1 7 ± ± 2 ± ±
: 33
± %) 5 ± 7 7 ± 7 0.5
7 % 2 6
)

PAF: paroxysmal atrial fibrillation; PerAF: persistent atrial fibrillation; CAD:

coronary artery disease; BMI: Body Mass Index, LAD: left atrial diameter; LVEF:
left ventricular ejection fraction; SBP: systolic blood pressure; GFR: glomerular
filtration rate, AAD: antiarrhythmic drug.

Table 3 Pooled demographic features of the included patients

overall PVI PVI+RDN P value

Sample size 387 222 165

Age 57±10 57.6±10.8 57.2±8.9 0.69

Male 275 (71%) 155 (70%) 120 (72%) 0.53

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 Paroxysmal AF 279 (72%) 171 (77%) 108 (66%) 0.01

Persistent AF 108 (28%) 51 (23%) 57 (35%) 0.06

History of AF 4.1±2.6 3.9±2.3 4.4±3 0.07

Accepted Article

Diabetes 87 (22%) 55 (25%) 32 (19%) 0.21

CAD 35 (9%) 19 (9%) 16 (10%) 0.70

BMI 26.5±4.7 26.8±5.2 26.2±3.9 0.19

LAD 44±8 43.6±8.2 44.6±7.6 0.22

LVEF 57.4±6.9 56.6±7 58.4±6.6 0.01

SBP 145±25 142±25 150±24 0.001

eGFR 66±14.3 64±14.4 68±14 0.006

AADs 3.5±1.1 3.5±1.1 3.5±1.1 1.0

CAD: coronary artery disease; BMI: Body Mass Index, LAD: left atrial diameter;

LVEF: left ventricular ejection fraction; SBP: systolic blood pressure;

GFR: glomerular filtration rate, AAD: antiarrhythmic drug.

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 Table 4 Meta-Regression analysis based on demographic variables against AF
recurrence

Variables Slope Point-Estimate [lower limit to upper limit] P value

Age 0.063 [-0.188 to 0.315] 0.620

Accepted Article

Gender -2.940 [-9.099 to 3.217] 0.349

Type of AF 0.343 [-1.055 to 1.741 0.630

History of AF -0.496 [-1.540 to 0.547] 0.351

Diabetes 1.230 [-2.620 to 5.080] 0.531

CAD -6.987 [-31.564 to 17.591] 0.577

BMI -0.256 [-0.749 to 0.237] 0.309

Baseline LAD -0.006 [-0.117 to 0.105] 0.916

Baseline LVEF -0.036 [-0.118 to 0.047] 0.398

Baseline BP -0.008 [-0.030 to 0.013] 0.445

Baseline eGFR -0.012 [-0.047 to 0.023] 0.505

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 Baseline AADs -0.305 [-1.363 to 0.753] 0.572

CAD: coronary artery disease; BMI: Body Mass Index, LAD: left atrial diameter;

LVEF: left ventricular ejection fraction; BP: blood pressure;

Accepted Article
GFR: glomerular filtration rate, AAD: antiarrhythmic drug.

Table 5 Effect of RDN on blood pressure and procedural complications

Significan
P value
ce of
of BP
reductio BP RDN
Change of BP
Sampl n reduction procedural
Follo relative to
Study for
e size w up baseline (mm compar complicatio
Hg) before-aft
ed to ns
er
non-RD
comparis
N
on

systoli diastoli
12
JACC RDN: c BP c BP Significan
mont P<0.001 None
2012 13 t
hs -25±5 -10±2

Heart systoli diastoli

12
Rhyth RDN: c BP c BP Significan
mont P<0.01 None
m 41 t
hs
2014 -20±7 -10±3

6
JICE RDN:
mont Controlled BP // // None
2016 39
hs

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 Cardi Change of mean
12
o RDN: artery pressure Significan
mont P<0.05 None
Thera 39 t
hs
2017 -7.5±3

24
Accepted Article
24
systoli
diastoli
12 c
JICE RDN: c Significan
mont ABP P<0.01 None
2018 33 ABPM t
hs M
10±2
-9±2

Office Office
systoli diastoli
[Poole c: -21 c -10±
12 ±7 2.7 P<0.01
d Significan
165 mont None
effect t
hs Mean Mean P<0.01
s] systoli diastoli
c: -8 c: -8.6
±2.6 ±3

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 Table 6 Summary of experimental studies investigating the effects of RDN on AF

Studies Experiment Model /setting Main findings

Accepted Article

Hypertension. Pigs, obstructive sleep RDN reduced negative tracheal

2012;60:172-178 [31] apnea-associated AF model pressure induced AF inducibility

J Interv Card Electrophysiol.

Dogs, atrial pacing model RDN decreased AF episodes
2012;35(2):119-25 [32]

Int J Cardiol. Dogs, ventricular pacing RSD suppressed atrial substrate

2013;168(2):1672-3 [33] heart failure model remodeling and AF vulnerability

J Cardiovasc Electrophysiol,
Pigs, atrial pacing model RDN reduced AF inducibility
2013;24(9):1028-33 [34]

PLoS One. 2013;8(5):e64611

Dogs, atrial pacing model RDN suppressed atrial remodeling
[35]

Dogs, left stellate ganglion

PLoS One. 2013;8(11):e78218
and rapid atrial pacing RDN reduced AF inducibility
[36]
model

RSD reversed atrial electrical

Dogs, ventricular pacing
PACE 2014; 37:1357–66 [37] remodeling and decrease AF
heart failure model
inducibility

Europace. 2015;17(4):647-54 RDN inhibited progression of

Dogs, atrial pacing model
[38] paroxysmal AF

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 RDN reduces atrial sympathetic
Circ Arrhythm Electrophysiol.
Goats, atrial pacing model nerve sprouting, structural
2015;8:466-74 [39]
alterations, and AF complexity

RDN reduced AF inducibility,

PLoS One. Dogs, renal impairment
prevented atrial
Accepted Article

2015;10(4):e0124123 [40] model

electrophysiological changes

Int J Cardiol. Dogs, acute atrial ischemia

RDN reduced new-onset AF
2016;203:187-95 [41] model

PLoS One. RDN suppressed AF inducibility

Rabitts, atrial pacing model
2016;11(8):e0160634 [42] and atrial fibrosis

Int J Cardiol. Rabbits, ventricular pacing RDN regulated atrial substrate,

2017;235:105-113 [43] heart failure model reverse structural remodeling

RDN suppressed AF inducibility,

J Am Heart Assoc. Rabbits, ischemic heart
reversed atrial electrical and
2018;7:e007312 [44] Failure model
structural remodeling

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