Varunsiri Atti ORCID iD: 0000-0002-0151-1545

Renal Sympathetic Denervation Improves Clinical Outcomes In

Accepted Article
Patients Undergoing Catheter Ablation For Atrial Fibrillation And

History Of Hypertension: A Meta-analysis

Varunsiri Atti, MD1, Mohit K Turagam, MD2, Jalaj Garg, MD2, Dhanunjaya Lakkireddy,

MD3

1- Michigan State University-Sparrow Hospital, East Lansing, MI.

2- Helmsley Electrophysiology Center, Icahn School of medicine at Mount Sinai,

New York City, NY.

3- Kansas City Heart Rhythm Institute and Research Foundation, Kansas City,

Kansas.

Funding: None

Disclosure: None

Corresponding author:
Varunsiri Atti, MD

Clinical center, 788 Service road

East Lansing, MI, 48824.

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.13868.

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 PH: 517-507-1328

Fax: 517-432-2759

Electronic address: varunsiri7@gmail.com

Accepted Article
Abstract

Background: Currently, there is limited data regarding the impact of adjunctive renal

sympathetic denervation (RSDN) with pulmonary vein isolation (PVI) in hypertensive

patients with atrial fibrillation (AF).

Methods: A comprehensive literature search for studies comparing RSDN+PVI vs. PVI -

alone for AF and history of hypertension until January 1st, 2019 was performed. The

results were expressed as risk ratio (RR) for the categorical variables and mean difference

(MD) for the continuous variables with 95% confidence intervals (CIs).

Results: A total of 6 eligible (4 randomized and 2 prospective non-randomized) studies

consisting of 432 patients (306 paroxysmal AF, 126 persistent AF) were included

(RSDN+PVI group-186 patients and PVI group-246 patients). Follow up ≥1 year.

Compared with PVI, RSDN+PVI significantly decreased the risk of AF recurrence RR

0.58, 95% CI (0.47 - 0.72, p<0.00001) on follow up. Fluoroscopy [MD +5.53 min. 95%

CI (0.76 - 10.31, p=0.02] and procedure time [MD +34.85 min. 95% CI (23.55 - 46.16,

p<0.00001)] was significantly longer with the PVI+RSDN group compared with PVI-

alone. There were no significant differences in complications between both groups. Test

of heterogeneity was low for all clinical outcomes (I2=0%).

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 Conclusion: Our meta-analysis demonstrates that RSDN as an adjunct to PVI appears to

be safe and improves clinical outcomes in both paroxysmal and persistent AF and history

of hypertension
Accepted Article
Keywords: Atrial fibrillation, hypertension, renal sympathetic denervation, pulmonary

vein isolation, atrial fibrillation recurrence.

Introduction

Atrial fibrillation (AF) is the most common arrhythmia worldwide and the

estimated global age adjusted prevalence was 0.5% in 2010, representing nearly 33.5

million individuals.1,2 The prevalence is still underestimated as a large proportion of

asymptomatic individuals and those having transient symptoms remain undiagnosed.2

Hypertension is the most common comorbidity that coexists with AF.3,4 Interaction

between an overactive sympathetic nervous system and hypertension is knowns to be

associated with progression of AF.5 This avenue of potential therapeutic overlap led to

the exploration of concomitant renal sympathetic denervation (RSDN) and pulmonary

vein isolation (PVI) by catheter based ablation for the treatment of anti-arrhythmic drug

resistant AF. Despite, carefully performed randomized controlled trials, the results

supporting RSDN as an adjunctive strategy to PVI for AF has been inconclusive. . In this

context, we performed a meta-analysis of all the studies published to date to evaluate the

efficacy and safety of concomitant RSDN and PVI in patients with drug-refractory AF.

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 Methods

Search strategy
Accepted Article
The systematic review and meta-analysis was done in compliance with PRISMA

(Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines.6 The

initial search strategy was developed by two authors (V.A and M.K.T). We performed a

systematic search, without language restriction, using PubMed, EMBASE, SCOPUS,

Google Scholar, and ClinicalTrials.gov from inception to January 1st, 2019 for studies

comparing RSDN plus PVI versus PVI alone. We used the following keywords: renal

sympathetic denervation, RSDN, renal denervation, sympathetic denervation,

radiofrequency ablation, RFCA, catheter ablation, atrial fibrillation, AF, hypertension,

and drug resistant hypertension.

Study Selection

The eligibility criteria for our systematic review were: 1) human subjects aged

≥18 years, 2) evaluated the safety and efficacy of RSDN+PVI versus PVI alone, 3)

reported at least one clinical outcome. We included studies published in English

language. All studies without a comparator arm and studies that did not report clinical

outcomes were excluded from our analysis.

Data Extraction

Two investigators (V.A and MKT) independently performed a literature review

and screened abstracts and full text versions of all the studies that met inclusion criteria.

Any discrepancy between the two was resolved by mutual consensus. The following data

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 were extracted: study title, sample size, type of study, patient characteristics including

age, comorbid conditions, baseline blood pressure measurements, echocardiographic

parameters including LVEF, left atrial size, follow up duration, AF recurrence,

Accepted Article
fluroscopy time, total procedure time and complications.

Clinical Outcomes

We evaluated the following clinical outcomes: 1) recurrence of AF, 2) procedure

time, 3) fluoroscopy time and 4) complications. We used the longest available follow-up

data from individual studies for our analysis.

Statistical Analysis

Statistical analysis was performed using random-effects model estimating the risk

ratio (RR) and 95% confidence interval (CI) obtained by Mantel-Haenszel method. The

results were expressed as risk ratio (RR) for categorical variables and mean difference

(MD) for continuous variables with 95% confidence intervals (CIs). Heterogeneity was

assessed using Higgins and Thompson’s I2 statistic, with I2 values <25%, 25% to 50%,

and >50% corresponding to mild, moderate and severe heterogeneity respectively.7 A 2-

tailed p < 0.05 was considered statistically significant for all analyses. Statistical analysis

was performed using Stata 11 (Stata Corp., College Station, Texas) and RevMan version

5.02 (Nordic Cochrane Center, Copenhagen, the Netherlands).

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 Results

Search results
Accepted Article
We identified a total of 106 relevant citations. PRISMA flow chart for study

extraction is presented in Figure 1. Six studies met the inclusion criteria of which, four

were randomized8-11 and two were prospective non-randomized studies.12,13 Among 432

patients, 186 underwent RSDN+PVI and 246 underwent PVI. Baseline characteristics of

included studies are presented in Table 1.

Study characteristics

Among the included studies, 306 patients had paroxysmal AF and 126 patients

had persistent AF. Mean (SD) of age ranged from 56 (6) to 68 (9) years. Mean (SD) of

left atrial diameter ranged from 44.9 (3.9) to 50 (6) millimeters. Mean (SD) left

ventricular ejection fraction (%) ranged from 60 (4) to 66.5 (10). Follow-up period

ranged from 12 months to 22.4±12.1 months. We used the Cochrane risk bias assessment

tool to assess the risk of bias among the included studies. The studies were classified as

low-risk, high-risk or unclear-risk, Table 2.

Clinical Outcomes

Recurrence of AF was significantly lower in RSDN+PVI group compared with PVI alone

(36% versus 63%, respectively; RR: 0.58, 95% CI: 0.47 - 0.72, p< 0.00001). RSDN+PVI

was associated with significantly higher procedure time (MD: +34.85, 95% CI: 23.55 -

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 46.16, p< 0.00001) and fluoroscopy time (MD: +5.53, 95% CI: 0.76 - 10.31, p= 0.02)

compared with PVI alone. There was no significant difference in complications (1

pericardial effusion in PVI group and none in RSDN+PVI) in both groups (p=0.48). Test
Accepted Article
of heterogeneity was low for all the clinical outcomes (I2= 0%). (Figure 2, 2.1 to 2.4).

Publication bias: As the number of included studies was less than 10, publication bias

was not performed.

Discussion

The main findings of our study include the following: 1) AF recurrence was

significantly lower in RSDN+PVI versus PVI alone, 2) procedure time and fluoroscopy

time was significantly higher in RSDN+PVI compared to PVI alone. 3) Complications in

both groups were low, with no significant difference.

Hypertension and AF are the two most common cardiovascular conditions with

rising prevalence throughout the world. Hypertension and AF share a reciprocal cause

and effect relationship.14 Cardiac sympathetic overdrive has been found to be one of the

contributing factors responsible for triggering and progression of AF.15 Blood pressure

elevation has been associated with increased atrial stretching and dilation resulting in

deleterious atrial electrical conduction promoting AF.16 This overlap of cardiovascular

risk factors and contributing pathophysiology between drug resistant AF and

hypertension represents a potential opportunity to explore therapeutic avenues with

synergistic benefit. Over the years, multiple adjuvant treatments have been developed for

atrial substrate modification during treatment of drug refractory AF. Among these,

modulation of cardiac autonomic innervation was found to be associated with increased

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 success of PVI.17 RSDN, a sympathetic modulation procedure has been an effective

therapeutic option for patients with drug resistant hypertension after promising results

were demonstrated in SIMPLICITY hypertension trials with BP reduction up to 25 mm-

Accepted Article
hg at 1 year.18,19 This led to the evaluation of RSDN as a possible antiarrhythmic

intervention for AF. Earlier investigators combined RSDN with PVI and demonstrated its

technical feasibility However, its efficacy remained uncertain.8,9

In our analysis, we found that only 36% of the patients who received RSDN+PVI

had recurrent AF, compared with 63% among those who received PVI alone. This

translated into nearly 40% reduction in the burden of recurrent AF with RSDN+PVI

compared with PVI alone. This finding of reduction in the burden of AF with

RSDN+PVI was consistently demonstrated across all the studies included in our analysis

with variation in the magnitude of benefit. The mechanism of RSDN induced reduced

burden of AF has been demonstrated in animal models. Wang et al and Linz et al showed

that RSDN prevented atrial electrophysiological changes, improved fibrosis, reduced

atrial sympathetic nerve sprouting in addition to blood pressure control.20,21 It was also

hypothesized that optimal blood pressure control influences atrial substrate preventing

recurrence of AF.8 Romanov et al showed a positive correlation between BP reduction

and decline in the burden of AF. It has been suggested that a 5-10 mmHg reduction in

mean BP was associated with nearly 7% decrease in the mean burden of AF.11All these

physiological changes explain the low recurrence of AF among patients receiving

RSDN+PVI. Furthermore, concomitant RSDN with PVI appears safe. No complications

have been reported in patients undergoing RSDN+PVI among the included studies.

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 Finally, our results reiterate the clinical benefit and safety associated with

concomitant RSDN during PVI in patients with drug-refractory AF and hypertension.

Thus, expanding the clinical indications of RSDN remains an exciting approach to be

Accepted Article
considered in the treatment of drug refractory AF. However, current evidence stems from

studies with relatively smaller sample size. Future RCTs should be adequately powered

to detect the true clinical benefits associated with RSDN+PVI. There are currently three

ongoing RCTs to assess the benefits of concomitant RSDN and PVI. (i) The

ERADICATE-AF (Renal Artery Denervation In Addition to Catheter Ablation To

Eliminate Atrial Fibrillation, clinicaltrials.gov NCT01873352) randomized 300 patients

to RSDN+PVI or PVI alone with primary endpoint of antiarrhythmic drug freedom from

AF. (ii) RSDforPAF (Renal Sympathetic Denervation in Patients With Hypertension and

Paroxysmal Atrial Fibrillation, clinicaltrials.gov NCT01814111) randomized 100

participants with hypertension and AF to RSDN+PVI vs PVI alone. The primary

endpoint is change in burden of AF at 1 year. (iii) The ASAF trial: ablation of sympthetic

atrial fibrillation (clinicaltrials.gov NCT02115100) randomizes 138 hypertensive patients

with AF in 1:1 fashion to RSDN plus PVI versus PVI alone. The primary endpoint is AF

recurrence at the 12 months follow up.

Study Limitations:

First, small number of studies with small sample size included, the results might still be

underpowered to detect the true clinical benefits of RSDN. Second, there were

differences in the risk profile of study participants among the included studies. Third, the

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 follow up period among the included studies was short and clinical outcomes beyond 1

year were not reported. Finally, publication bias could not be assessed as the number of

included studies are <10.

Accepted Article
Conclusion

In conclusion, renal sympathetic denervation as an adjunct to pulmonary vein

isolation appears to be safe with significant reduction in AF burden in hypertensive

patients with history of paroxysmal and persistent AF.

Conflicts of interest

The authors declare that they have no conflict of interest.

Funding

No external sources of funding have been utilized for this systematic review and meta-

analysis

work.

Ethical approval

The manuscript has not been submitted or is under consideration elsewhere in any other

Journal.

No data has been fabricated or manipulated. Consent to submit has been received

explicitly from

all co-authors.

This article is protected by copyright. All rights reserved.

 Disclosure

Varunsiri Atti: None

Accepted Article
Mohit Turagam: None

Jalaj Garg: None

DJ Lakkireddy: None

References

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baseline data, and profile of patients according to chosen treatment strategy for

atrial fibrillation. Am J Cardiol. 2010;105(5):687-693.

4. Nabauer M, Gerth A, Limbourg T, et al. The Registry of the German Competence

NETwork on Atrial Fibrillation: patient characteristics and initial management.

Europace. 2009;11(4):423-434.

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 5. Linz D, Ukena C, Mahfoud F, Neuberger H-R, Böhm M. Atrial autonomic

innervation: a target for interventional antiarrhythmic therapy? J Am Coll Cardiol.

2014;63(3):215-224.
Accepted Article
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for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern

Med. 2009;151(4):264-269, W264.

7. Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool

for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

8. Pokushalov E, Romanov A, Corbucci G, et al. A randomized comparison of

pulmonary vein isolation with versus without concomitant renal artery

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outcomes of catheter ablation in patients with atrial fibrillation and hypertension:

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11. Romanov A, Pokushalov E, Ponomarev D, et al. Pulmonary vein isolation with

concomitant renal artery denervation is associated with reduction in both arterial

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 blood pressure and atrial fibrillation burden: Data from implantable cardiac

monitor. Cardiovasc Ther. 2017;35(4).

Accepted Article
12. Kiuchi MG, Chen S, GR ES, et al. Pulmonary vein isolation alone and combined

with renal sympathetic denervation in chronic kidney disease patients with

refractory atrial fibrillation. Kidney Res Clin Pract. 2016;35(4):237-244.

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to pulmonary vein isolation reduces recurrence of paroxysmal atrial fibrillation in

chronic kidney disease patients. J Interv Card Electrophysiol. 2017;48(2):215-

222.

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hypertension. Pharmacol Res. 2018;128:322-326.

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Creation of Substrate for Atrial Fibrillation. Circ Arrhythm Electrophysiol. 2012.

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Curr J Rev. 2004;13(5):65.

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 18. Elliott WJ. Catheter-based renal sympathetic denervation for resistant

hypertension: a multicentre safety and proof-of-principle cohort study. Yearbook

of Cardiology. 2010;2010:55-56.
Accepted Article
19. Widdop R. Faculty of 1000 evaluation for Percutaneous renal denervation in

patients with treatment-resistant hypertension: final 3-year report of the

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21. Linz D, van Hunnik A, Hohl M, et al. Catheter-based renal denervation reduces

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Electrophysiol. 2015;8(2):466-474.

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 Tables

Table 1: Baseline characteristics of included studies.

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Study Stu Study Sam Age Type of Baseline Left atrial LVEF (%) Follo
dy design ple AF Blood w up
per size pressur diameter RSDN PVI
iod e (mon
RSDN SBP/DB RSDN PVI +PVI ths)
PVI P
+PVI
+PVI
(mm.
Hg)
(RSDN
+PVI
vs. PVI)

Pokush NR RCT 1 1 57±8 Paroxysmal 181±7 49±7 50±6 65±5 66±4 12

alov, 3 4 vs 33% /97±6
2012
56±9 Persistent vs

66% 178±8//9
6±4

Pokush NR RCT 4 3 56±6 Paroxysmal 163±18/ 47±5 47±4 60±4 61±5 12

alov, 1 9 43.75% 89±11
2014 vs vs
Persistent-
56±6 56.25% 164±17/
88±11

Kiuchi, 201 Prospe 2 2 68±9 Paroxysmal 119±7/8 45.1 44.9 62.7± 63.6 12
2016 4- ctive 1 4 60% 0±3 ±3.2 ±3.9 6.6 ±6.8
201 non- vs
5 rando Persistent vs
mized 66±9
40% 117±8/7
9±3

Roman 201 RCT 3 3 56±6 Paroxysmal 163±20/ 47±6 47±5 60±4 61±4 12
ov, 0-

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 2016 201 9 7 vs 40.7% 88±13
3
56±5 Persistent5 vs
9.3%
164±16/
Accepted Article
88±12

Kiuchi, 201 Prospe 3 9 60±1 Paroxysmal 121±9/7 NR NR 65.8± 66.5 22.4±

2017 2- ctive 9 6 4 100% 9±6 12.8 ±10 12.1
201 non-
5 rando vs vs
mized
59±1 119±8/7
5 9±8

Kiuchi, 201 RCT 3 3 56.8 Paroxysmal 142±6 NR NR 62.2± 61.2 12

2018 4- 3 6 ±6.5 100% 7.2 ±5.7
201 vs
5 vs
140±6
58.4
±5.1

Abbreviations: - RCT- Randomized controlled trial; RSDN- Renal sympathetic denervation; PVI-
Pulmonary vein isolation; AF- Atrial fibrillation; SBP- Systolic blood pressure; DBP- Diastolic blood
pressure; LVEF- Left ventricular ejection fraction;

Table 2: Detailed risk bias assessment using the Cochrane risk of bias tools.

Pokushalov, Pokushalov, Kiuchi, Romanov, Kiuchi, Kiuchi,

Bias types
2012 2014 2016 2016 2017 2018

Selection
High- Unclear- Unclear- Unclear-
bias Unclear-risk Unclear-risk
risk risk risk risk
Random
sequence
generation High- Unclear- Unclear- Unclear-
Unclear-risk Unclear-risk
risk risk risk risk
Allocation

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 concealment

Performance
bias
Accepted Article
Blinding of
High- High- High-
participants High-risk High-risk High-risk
risk risk risk
and
personnel

Detection
bias

Blinding of High- Unclear- High- Unclear-

Unclear-risk Unclear-risk
outcome risk risk risk risk
assessment

Attrition
bias Low- Low- Low-
Low-risk Low-risk Low-risk
risk risk risk
Incomplete
outcome data

Reporting
bias

Selective Low- Low- Low-

reporting Low-risk Low-risk risk Low-risk risk risk

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 Figures

Figure 1: Search strategy and selection criteria of included studies

Accepted Article

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Accepted Article Figure 2: Forest plot of study outcomes.

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