Renal Denervation Suppresses Atrial Fibrillation in a Model of Renal Impairment
Renal Denervation Suppresses Atrial Fibrillation in a Model of Renal Impairment
Zhuo Liang 0 1
Xiang-min Shi 0 1
Li-feng Liu 0 1
Xin-pei Chen 0 1
Zhao-liang Shan 0 1
Kun Lin 0 1
Jian Li 0 1
Fu-kun Chen 0 1
Yan-guang Li 0 1
Hong-yang Guo 0 1
Yu-tang Wang 0 1
0 Academic Editor: Jaap A. Joles, University Medical Center Utrecht , NETHERLANDS
1 1 Department of Cardiology, Chinese PLA General Hospital , Beijing , China , 2 Department of Emergency, Beijing Tsinghua Changgeng Hospital Medical Center, Tsinghua University , Beijing , China , 3 Department of Geriatric Cardiology, Chinese PLA General Hospital , Beijing , China
Embolization of small branches of the renal artery in the right kidney led to ischemic RI.
Heart rate, P wave duration and BP were increased by RI, which were prevented or
attenuated by RDN. Atrial effective refractory period was shortened and AF inducibility was
increased by RI, which were prevented by RDN. Antegrade Wenckebach point was
shortened, atrial and ventricular rates during AF were increased by RI, which were
attenuated or prevented by RDN. Levels of norepinephrine, renin and aldosterone in plasma,
norepinephrine, angiotensin II, aldosterone, interleukin-6 and high sensitivity C-reactive protein in
RDN significantly reduced AF inducibility, prevented the atrial electrophysiological changes
in a model of RI by combined reduction of sympathetic drive and RAAS activity, and
inhibition of inflammation activity and fibrotic pathway in atrial tissue.
Patients with chronic kidney disease (CKD) show a high prevalence of atrial fibrillation (AF)
[1,2,3]. Exploring the inherent pathogenic mechanisms responsible for the development of AF
among CKD patients and identifying effective therapeutic targets are urgent. CKD is
accompanied by ischemic renal impairment (RI) and renal dysfunction. The ischemic RI lead to
increased sympathetic activation . Hyper-sympathetic activity is involved in atrial remodeling
processes [5,6]. The renin-angiotensin-aldosterone system (RAAS) is also activated by renal
ischemic impairment and increased sympathetic activation in CKD , and angiotensin II and
aldosterone create a substrate for AF [8,9]. Previously, we showed that AF was associated with
RI with mild renal insufficiency and increased activity of the sympathetic nervous system
(SNS) and RAAS may contribute to the development of AF associated with RI with mild renal
insufficiency in animal experiment . However, intervention measures to inhibit the activity
of SNS or RAAS need to be further applied. It will be important for elucidating mechanisms
and developing new therapeutic strategies for CKD-induced atrial
We hypothesized that modulation of the SNS might reduce AF susceptibility in CKD. Renal
denervation (RDN), which is a new therapeutic approach to treat resistant hypertension
through reducing renal norepinephrine spillover, can also reduce susceptibility to AF in animal
models of obstructive sleep apnea and heart failure by reduction of sympathetic drive, RAAS
activity and atrial fibrosis [11,12,13]. However, the effect of RDN after RI on AF inducibility is
unknown. In this study, unilateral diffuse ischemic RI was induced in dogs by transcatheter
embolization of small renal artery branches using gelatin sponge granules. By treating dogs
with RDN, the role of sympathetic activation for AF vulnerability associated with RI was
specifically addressed. Effects of RDN on RAAS activation, atrial inflammation and fibrosis in dogs
with RI were also explored.
This study was carried out in strict accordance with the recommendations in the Guide for the
Care and Use of Laboratory Animals of the National Institutes of Health (Publication No. 85
23, revised 1996). The protocol was approved by the Institutional Animal Care and Use
Committee of the Chinese PLA General Hospital.
The experimental animals included 18 healthy, 5-year-old beagles weighing 1012 kg. All dogs
were anesthetized with intravenous sodium pentobarbital (20 mg/kg) and were intubated using
an endotracheal tube and mechanical ventilation. Heart rate and rhythm were monitored by a
continuous 3-lead electrocardiogram. A 6F sheath was placed in the right femoral artery.
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were monitored via the sheath
using an invasive blood pressure (BP) monitor. A pigtail catheter was introduced into the left
ventricle (LV) through the arterial sheath to detect LV end-diastolic pressure (LVEDP).A bolus
of heparin (4000 IU) was administrated through the sheath to prevent thromboembolism.
At baseline, an electrocardiogram, BP and LVEDP were monitored. Electrophysiological
examinations were performed. Plasma parameters were measured. Then dogs were divided into
three groups. Group 1 (n = 6) served as a control (Sham). In group 2 (n = 6), RI was induced
(Model). In group 3 (n = 6), RDN was performed after RI (RDN). After 2 weeks of feeding, the
same parameters measured at baseline were measured and renal artery angiography was
performed again. Creatinine clearance (CCr) was determined by 30-min endogenous creatinine
clearance method . Dogs were then sacrificed humanely by an intravenous overdose of
thiopental (2 g). Hearts and right renal arteries were removed for further histology analysis.
Experimental model for RI
A 5F multifunction catheter was introduced through the arterial sheath and renal artery
angiography was performed under fluoroscopy. Following renal artery angiography, RI was
induced in dogs by transcatheter embolization of small branches of the right renal artery using
gelatin sponge granules (diameter ~50 m, 3040mg), whereas the main renal artery or
subsegment renal artery was kept fluent . In the Sham group, normal saline was injected into
the renal artery after renal artery angiography as a sham procedure.
In the RDN group, a 6F ablation catheter (Biosense Webster, Inc., Diamond Bar, CA, USA)
was introduced into the right renal artery via the femoral artery. The tip of the catheter was
positioned under direct vision to ensure that it was placed accurately in the renal artery. The renal
artery was divided into four areas, from the ostia to the area near the bifurcation based on
angiographic imaging. Each discrete radiofrequency ablation (6 watts) lasted up to 80 s, for a total
four ablations longitudinally and circumferentially within the four areas of the right renal
artery . In the Sham and Model groups, the catheters were introduced into the right renal
artery, without ablation being performed.
The right femoral vein was cannulated for catheter insertion. The tip of a multielectrode
catheter was placed on the lateral right atrium to record right atrial potentials and to induce rapid
atrial pacing. A train of eight basic stimuli (S1, pulse duration 1 ms) at twice the diastolic
pacing threshold was followed by an extra stimulus (S2). The atrial effective refractory period
(AERP) was defined as the longest S1S2 interval that failed to elicit a propagated atrial
response. The AERP was measured at basic pacing cycle lengths of 300 ms and 240 ms, and the
S1S2 intervals were decreased from 200 ms to refractoriness by decrements of 5 ms
(LEAD7000, multi-channel physiology recorder; Sichuan Jinjiang Electronic Science and Technology
Co., Ltd, Sichuan, China). The longest cycle length of atrial pacing causing second-degree
atrioventricular nodal block (antegrade Wenckebach point) was determined. After the AERP and
antegrade Wenckebach point were determined, rapid atrial pacing (60 ms of basic cycle
lengths, 10 s in duration, four-fold threshold current) was delivered for 10 times to induce AF
(DF-5A, heart stimulator; Suzhou Dongfang Electronic Instruments Plant, Jiangsu, China). AF
was defined as irregular atrial rates (cycle length <200 ms; duration >5 s) with irregular
atrioventricular conduction. AF inductibility was defined as (the relative ratio of successful
induction frequency to total frequency of pacing in each group) 100%. All AA-and RR-intervals
during AF were calculated to determine the mean atrial and ventricular rates during AF.
Plasma measurements and urinalysis
Blood samples were collected from the femoral vein into tubes containing EDTA, and
immediately centrifuged at 2310 g for 10 minutes at 4C, and then finally stored at -80C until further
assay. Levels of norepinephrine, renin, aldosterone and creatinine in plasma and creatinine in
urine were examined by ELISA (Wuhan Beinglay Biotech Co., Ltd., Hubei, China).
Renal arteries with their perivascular tissues were removed and immediately dissected and
fixed in formaldehyde. A month later, the renal arteries with their perivascular tissues were
stained with hematoxylin-eosin (HE) to observe the structure of the renal arteries and renal
sympathetic nerves in the three groups. The renal arteries with their perivascular tissues were
cut into four parts transversely from the ostia to the area near the bifurcation. Each part was
fixed, embedded in paraffin, and sliced into sections (5 m thickness) of which 10 were taken
from each part and processed. All sections were stained with H&E. Sections from each part
with the most injured nerves were examined and the total number of nerves and the number of
injured nerves were recorded. The distance from the nerves to the renal artery lumen-intima
interface was also measured. Left atria were carefully removed. Part of atrial tissue was fixed in
10% phosphate-buffered formalin, and embedded in paraffin. Deparaffined sections (5 m
thickness) were stained with Massontrichrome. Connective tissue was differentiated on the
basis of its color (blue) and expressed as a percentage of the reference tissue area using
ImagePro Plus 4.5. In each atrium, 3 images with a magnification of 400 were analyzed and
averaged. Part of atrial tissue was stored at -80C until further assay. Levels of norepinephrine,
angiotensin II, aldosterone, interleukin-6 (IL-6) and high sensitivity C-reactive protein (hs-CRP)
in atrial tissue were examined by ELISA (Wuhan Beinglay Biotech Co., Ltd., Hubei, China).
Values are shown as mean SD. For comparisons of single repeatedmeasures only, a paired
Student t test was used. Differences of the changes in value between two weeks and the baseline
among the three groups were subjected to ANOVA followed by the Dunnet test. ANOVA was
also used followed by the Dunnet test to compare differences of norepinephrine, angiotensin
II, aldosterone, IL-6, hs-CRP and interstitial fibrosis in atrial tissue and CCr among the three
groups. The chi-square test was used to compare the AF induction rate. P<0.05 was considered
Right renal artery angiography was performed before (Fig 1A) and after (Fig 1B) transcatheter
embolization in the RDN group. Small renal artery branches were occluded after transcatheter
embolization, whereas the main renal artery or sub-segment renal artery remained fluent. Fig
1C shows representative images of ablation using 6F ablation catheter in the right renal artery
Fig 1. Fluoroscopic images of the right renal artery. Images of the right renal artery angiography before
transcatheter embolization (A) and after transcatheter embolization (B) in RDN group. Images of ablation
catheter which was placed in the right renal artery after renal impairment for ablation (C). Images of the right
renal artery angiography after 2 weeks of ablation (D).
after RI. The right renal artery had no obvious stenosis after 2 weeks of ablation (Fig 1D). The
CCr in the Model and RDN groups were slightly decreased by 22.2% and 26.4% separately
compared with the Sham group after 2 weeks of RI (P < 0.05 for each). There was no difference
of CCr between the Model and RDN groups. Fig 2 shows representative images of HE staining
of the right renal artery and renal sympathetic nerves (arrow indicated) with different
magnification in the RDN (B, D) and Model (A, C) groups respectively. Renal sympathetic nerves were
intact and surrounded by outer membrane in the Model group. On the contrary, renal
sympathetic nerves were damaged in the RDN group, which had contracted morphology and lost
surrounding outer membrane. Approximately 49% of renal nerves observed exhibited injury due
to the RDN procedure (n = 96 of 196). More than 90% of renal nerves were found between
1.03.0mm from the renal artery lumen-intima interface and about 90% of the injured nerves
were found in this range. The impedance decreased from 252.532.5O to 233.830.6O
(P < 0.05, n = 24) after ablation in the RDN group.
Effects of RDN on ECG, BP and LVEDP
Sham operation did not change the heart rate, P wave duration, systolic and diastolic blood
pressure after 2 weeks, compared with the baseline values in the Sham group. In contrast, 2
weeks of RI induced a pronounced increase in heart rate, P wave duration, systolic blood
Fig 2. Hematoxylin-eosin (HE) staining images of the right renal artery and renal sympathetic nerves. Images of HE staining of the right renal artery
and renal sympathetic nerves (arrow indicated) with a magnification of 40 in the Model (A) and RDN (B) groups. Images of HE staining of the renal
sympathetic nerves (arrow indicated) with a magnification of 100 in the Model group (C) and RDN groups (D).
pressure and diastolic blood pressure by 22.5%, 12.9%, 18.2% and 16.4% respectively,
compared with the baseline values in the Model group (P < 0.05 for each). RDN reduced
RI-induced heart rate increase, systolic blood pressure increase and diastolic blood pressure increase
by 50.5%, 55.8% and 55.4%, respectively (P < 0.05 for each) (Fig 3A, 3C and 3D). RDN
completely prevented RI-induced P wave duration increase (P < 0.05) (Fig 3B). LVEDP was
unchanged significantly after 2 weeks, compared with the baseline values in the three groups.
Effects of RDN on AERP and AF Inducibility
Sham operation did not change the AERP at 300-ms or at 240-ms basic cycle lengths after 2
weeks, compared with the baseline values in the Sham group. In contrast, 2 weeks of RI
induced a pronounced AERP shortening at 300-ms basic cycle lengths and at 240-ms basic cycle
lengths by 10.8% and 7.4% respectively, compared with the baseline values in the Model group
(P < 0.05 for each). RDN completely prevented RI-induced AERP shortening at 300-ms basic
cycle lengths and at 240-ms basic cycle lengths (P < 0.05 for each) (Fig 4A and 4B). Sham
operation did not change the inducibility (Fig 5A) or duration of AF after 2 weeks, compared with
the baseline values in the Sham group. In contrast, 2 weeks of RI resulted in a significant
increase in AF inducibility by 1.5 fold (P < 0.05) (Fig 5B) and prolonged the duration of AF by
1.86 fold compared with the baseline values in the Model group (P < 0.05). The AF inducibility
was unchanged after 2 weeks, compared with the baseline values in the RDN group (P > 0.05)
(Fig 5C). RDN completely prevented RI-induced prolongation of AF duration (P < 0.05) (Fig
Fig 3. ECG and blood pressure analysis (n = 6). Effects of RDN on the RI-induced heart rate (A), P wave
duration (B), systolic blood pressure (C) and diastolic blood pressure (D) changes between values of 2 weeks
Sham operation did not change the Antegrade Wenckbach Point, arial or ventricular rates
during AF after 2 weeks, compared with the baseline values in the Sham group. In contrast, 2
weeks of RI induced a pronounced shortening of Antegrade Wenckbach Point by 11.2%, a
significant increase in atrial and ventricular rates during AF by 11.4% and 9.8% respectively,
compared with the baseline values in the Model group (P < 0.05 for each). RDN reduced
RIinduced Antegrade Wenckbach Point shortening by 87.2% (Fig 6A), and completely prevented
RI-induced increase in ventricular and atrial rates during AF (P < 0.05 for each) (Fig 6B and
Fig 4. Atrial effective refractory period (AERP) analysis (n = 6). Effects of RDN on RI-induced AERP
changes between values of 2 weeks and baseline at 300-ms basic cycle lengths (A) and at 240-ms basic
cycle lengths (B).
Fig 5. Analysis of the occurrence of AF (n = 6). The inducibility of AF in the Sham (A), Model (B) and RDN
(C) groups at baseline and 2 weeks. Effects of RDN on RI-induced changes of AF duration between values of
2 weeks and baseline (D).
Effects of RDN on the activity of SNS
Plasma noradrenaline levels were measured to represent systematic activity of SNS. Sham
operation did not change the plasma noradrenaline levels after 2 weeks, compared with the baseline
values in the Sham group. In contrast, 2 weeks of RI induced a significant increase in plasma
noradrenaline levels by 71.6%, compared with the baseline values in the Model group
(P < 0.05). RDN reduced RI-induced increase in plasma noradrenaline levels by 42.5%
(P < 0.05) (Fig 7A). Levels of noradrenaline in left atrial tissue were measured (Fig 7B).
Compared with the Sham group, levels of noradrenaline were increased in the Model group by
42.3% (P < 0.05). In the RDN group, levels of noradrenaline were reduced by 12.6%, compared
with the Model group P < 0.05).
Effects of RDN on the Activity of RAAS
Sham operation did not change the plasma levels of renin and aldosterone after 2 weeks, compared
with the baseline values in the Sham group. In contrast, 2 weeks of RI induced a pronounced
increase in plasma levels of renin and aldosterone by 56.2% and 59.9% respectively, compared with
the baseline values in the Model group (P < 0.05 for each). RDN reduced RI-induced increase in
plasma levels of renin and aldosterone by 47.3% and 57.1% respectively (P < 0.05 for each) (Fig
8A and 8B). Levels of angiotensin II and aldosterone in left atrial tissue were shown in Fig 8C and
8D, respectively. Compared with the Sham group, left atrial tissue levels of angiotensin II and
aldosterone were increased by 61.3% and 67.1% respectively in the Model group (P < 0.05 for each).
In the RDN group, levels of angiotensin II and aldosterone were reduced by 16.9% and 20%
respectively, compared with the Model group (P < 0.05 for each).
Fig 6. Analysis of the Antegrade Wenckebach point, atrial and ventricular rates during AF (n = 6). Effects of RDN on the changes of Antegrade
Wenckbach Point (A), ventricular (B) and atrial (C) rates during AF between values of 2 weeks and baseline.
Fig 7. Analysis of the activity of SNS. Effects of RDN on the changes of plasma noradrenaline levels between values of 2 weeks and baseline (A) (n = 6).
Left atrial noradrenaline levels in the three groups (B) (n = 6).
Effects of RDN on the inflammation
Left atrial tissue levels of hs-CRP and IL-6 were measured to represent the activity of
inflammation (Fig 9A and 9B). Compared with the Sham group, levels of hs-CRP and IL-6 were
increased by 61.4% and 73.8% respectively in the Model group (P < 0.05 for each). In the RDN
group, levels of hs-CRP and IL-6 were reduced by 21.9% and 22.6% respectively, compared
with the Model group (P < 0.05 for each).
Effects of RDN on the atrial fibrosis
Fig 10A, 10B and 10C illustrate representive images of Masson staining of the left atrial tissue
after 2 weeks of interventional operation in the Sham, Model and RDN groups, respectively.
The quantitative ratio of the area of interstitial fibrosis was summarized in Fig 10D. Compared
Fig 8. Analysis of the activity of RAAS. Effects of RDN on the changes of plasma levels of renin (A) and
aldosterone (B) between values of 2 weeks and baseline (n = 6). Left atrial angiotensin II (C) and aldosterone
(D) levels in the three groups (n = 6).
Fig 9. Analysis of the activity of left atrial inflammation (n = 6). Left atrial high sensitivity C-reactive
protein (A) and interleukin-6 (B) levels in the three groups.
with the Sham group (6.12.0%), extensive and heterogeneous interstitial fibrosis was observed
in the Model group (13.32.3% P < 0.05). The interstitial fibrosis induced by RI was attenuated
in the RDN group (8.51.1% P < 0.05).
This is the first reported experiment demonstrating that RDN could suppress RI-associated AF
occurrence. RDN also attenuated the RI-induced increase in SNS and RAAS activities as well
as atrial inflammation and fibrosis, which might contribute to AF occurrence in an RI model.
To date, only two animal studies have shown that RI is associated with the development of AF
[10,16]. A classic model of CKD was created in rats with 5/6 nephrectomy in which oxidative
stress might have been involved in the pathogenesis of interstitial fibrosis and enhanced
vulnerability to AF in the left atrium . We also established a large-animal model after 2 weeks of
ischemic RI with mild renal insufficiency that was associated with vulnerability to AF . In
Fig 10. Analysis of atrial fibrosis. Representive images of Masson staining of the left atrial tissue after 2
weeks of interventional operation in the Sham (A), Model (B) and RDN (C) groups. Mean percentage of
interstitial fibrosis of the left atrium in the three groups (D) (n = 6).
addition to the mechanism of oxidative stress, inflammation and RAAS and SNS activation are
predicted to play important roles in the development of CKD-associated AF . To date,
there have not been any published experimental studies to clarify these possible mechanisms
because of the lack of appropriate animal models.
Renal denervation is used to reduce renal norepinephrine spillover. It inhibits pronounced
shortening of the AERP and reduced susceptibility to AF in animal models of obstructive sleep
apnea and heart failure [11,12] by combined reduction of sympathetic drive and RAAS activity
In this study, we established an in vivo model of RI that is associated with vulnerability to
AF in a large animal (dogs). RDN was applied to demonstrate further that increased
sympathetic activation played an important role in RI-induced AF. RDN may be a promising
therapeutic strategy for CKD-induced atrial arrhythmogenic remodeling.
Accumulating evidence has shown that in injured kidneys afferent signals to central
integrative structures in the brain lead to increased sympathetic activation. Also, the sympathetic
nervous system plays an important role in the pathophysiology and progression of CKD .
RDN could completely normalize atrial systolic and diastolic pressure, the plasma
norepinephrine level, and the heart rate, which had been increased by renal injury in a rat model .
RDN reduced the RI-induced increase in the plasma norepinephrine level, heart rate, and
blood pressure significantly in our study, which is in accord with the results of a previous
study. LVEDP had not changed significantly after 2 weeks compared with baseline values in
any group in our present study. Our previous study also showed that hypertension did not
affect left atrial pressure, and its effect on vulnerability to AF was negligible in our model .
The effect of RDN on hypertension in our model, however, was still important. Although the
effect of RDN on resistant hypertension is still debatable , RDN may provide a new
therapeutic strategy for CKD-induced hypertension because this kind of hypertension is closely
related to the hypersympathetic activity induced by RI.
Previous studies have provided evidence that sympathetic activity is involved in the
initiation and maintenance of AF . Reducing cardiac sympathetic outflow by cryoablation of the
bilateral stellate ganglia and T2T4 thoracic ganglia can effectively eliminate paroxysmal atrial
tachyarrhythmia in dogs with pacing-induced heart failure . In our study, AF inducibility
was unchanged after 2 weeks compared with the baseline values in the RDN group, and RDN
completely inhibited RI-induced prolongation of AF duration. These results further
demonstrated that sympathetic activity plays an important role in AF associated with RI.
Overactivity of the SNS might play an important role in shortening the effective refractory
period because adrenergic stimulation alone can decrease the human AERP by approximately
5% . Although a previous study showed that RDN did not significantly influence AERP in
normal pigs , RDN completely inhibited RI-induced AERP shortening and RI-induced
increase in the atrial rate during AF in our study. These data predicted that RDN might influence
atrial electrical remodeling only when the autonomic nervous balance is disrupted. AERP
shortening induced by sympathetic activity in our RI model may contribute to AF occurrence
associated with RI.
It is well known that sympathetic overactivity shortens the antegrade Wenckbach point and
accelerates AV conduction, whereas vagal stimulation has the opposite effect . There has
been a report of reduced ventricular heart rate in a patient with permanent AF undergoing
RDN. Also, RDN has been reported to prolong the antegrade Wenckbach point and provided
rate control during AF in pigs . In our study, RDN reduced RI-induced antegrade
Wenckbach point shortening and completely inhibited any RI-induced increase in atrial and
ventricular rates during AF. Our data indicate that RDN could be promising strategy for rate control in
It is also well known that renal sympathetic stimulation induces renin release. The RAAS
can be activated by renal ischemic impairment and increased sympathetic activation in CKD
. The RAAS is involved in myocardial inflammation and fibrosis and creates a substrate for
AF [8,25]. In our study, RDN attenuated RAAS activation induced by RI in both the circulating
system and atrial tissue. RDN also attenuated atrial tissue inflammation and fibrosis induced
by RI and completely inhibited any increase in RI-induced P-wave duration. These results
indicated that the RAAS activated by increased sympathetic activation may also contribute to
RIassociated AF occurrence. The above data predicted that the hypersympathetic activity may be
a trigger that facilitates initiation of RI-associated AF and may be indirectly involved in the
activation of RAAS, atrial inflammation, and fibrosis.
The pathophysiological process and severity of renal impairment in our model is not
completely in accord with the real situation of CKD. Although RDN was applied immediately after RI in
our study, there should be a broader time window after RI and before RDN application in
future studies. Also, the effect of RDN on AF inducibility, atrial electrophysiological changes,
RIinduced hypertension, and renal function in our model needs to be assessed over the
We established a canine model of RI with mild renal insufficiency. Using this model, we
showed that hypersympathetic activity may facilitate the initiation of RI-associated AF because
RDN significantly reduces AF inducibility and shortens its duration. We also showed in our RI
model that hypersympathetic activity may be involved directly in atrial electrophysiological
changes and indirectly in the activation of RAAS, atrial inflammation, and fibrosis. RDN may
provide a new therapeutic strategy for CKD-induced atrial arrhythmogenic remodeling
Wrote the paper: ZLS KL.
Conceived and designed the experiments: ZL YTW HYG. Performed the experiments: ZL XMS
LFL XPC YGL. Analyzed the data: JL. Contributed reagents/materials/analysis tools: FKC.
1. Chen LY , Shen WK . Epidemiology of atrial fibrillation: a current perspective . Heart Rhythm . 2007 ; 4 : S1 -6. PMID: 17539194
2. Zimmerman D , Sood MM , Rigatto C , Holden RM , Hiremath S , Clase CM. Systematic review and metaanalysis of incidence, prevalence and outcomes of atrial fibrillation in patients on dialysis . Nephrol Dial Transplant . 2012 ; 27 : 3816 - 3822 . doi: 10.1093/ndt/gfs416 PMID: 23114904
3. Soliman EZ , Prineas RJ , Go AS , Xie D , Lash JP , Rahman M , et al. Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC) . Am Heart J . 2010 ; 159 : 1102 - 1107 . doi: 10.1016/j.ahj. 2010 . 03.027 PMID: 20569726
4. Schlaich MP , Socratous F , Hennebry S , Eikelis N , Lambert EA , Straznicky N , et al. Sympathetic activation in chronic renal failure . J Am Soc Nephrol . 2009 ; 20 : 933 - 939 . doi: 10.1681/ASN.2008040402 PMID: 18799718
5. Park HW , Shen MJ , Lin SF , Fishbein MC , Chen LS , Chen PS . Neural mechanisms of atrial fibrillation . Curr Opin Cardiol . 2012 ; 27 : 24 - 28 . doi: 10.1097/HCO.0b013e32834dc4e8 PMID: 22139702
6. Hou Y , Hu J , Po SS , Wang H , Zhang L , Zhang F , et al. 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 ; 8 : e78218. doi: 10.1371/journal. pone.0078218 PMID: 24223140
7. Siragy HM , Carey RM. Role of the intrarenal renin-angiotensin-aldosterone system in chronic kidney disease . Am J Nephrol . 2010 ; 31 : 541 - 550 . doi: 10.1159/000313363 PMID: 20484892
8. Mayyas F , Alzoubi KH , Van Wagoner DR . Impact of aldosterone antagonists on the substrate for atrial fibrillation: aldosterone promotes oxidative stress and atrial structural/electrical remodeling . Int J Cardiol . 2013 ; 168 : 5135 - 5142 . doi: 10.1016/j.ijcard. 2013 . 08.022 PMID: 23993726
9. Savelieva I , Kakouros N , Kourliouros A , Camm AJ . Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part II: secondary prevention . Europace . 2011 ; 13 : 610 - 625 . doi: 10.1093/europace/eur023 PMID: 21515595
10. Liang Z , Liu L , Chen X , Shi X , Guo H , Lin K , et al. Establishment of a Model of Renal Impairment with Mild Renal Insufficiency Associated with Atrial Fibrillation in Canines . PLoS ONE . 2014 ; 9 : e105974. doi: 10.1371/journal. pone.0105974 PMID: 25157494
11. Linz D , Mahfoud F , Schotten U , Ukena C , Neuberger HR , Wirth K , et al. Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea . Hypertension . 2012 ; 60 : 172 - 178 . doi: 10.1161/HYPERTENSIONAHA.112.191965 PMID: 22585944
12. Zhao Q , Yu S , Huang H , Tang Y , Xiao J , Dai Z , et al. Effects of renal sympathetic denervation on the development of atrial fibrillation substrates in dogs with pacing-induced heart failure . Int J Cardiol . 2013 ; 168 : 1672 - 1673 . doi: 10.1016/j.ijcard. 2013 . 03.091 PMID: 23597574
13. Linz D , Hohl M , Nickel A , Mahfoud F , Wagner M , Ewen S , et al. Effect of renal denervation on neurohumoral activation triggering atrial fibrillation in obstructive sleep apnea . Hypertension . 2013 ; 62 : 767 - 774 . doi: 10.1161/HYPERTENSIONAHA.113.01728 PMID: 23959548
14. Toshifumi W , Mika M. Effects of Benazepril Hydrochloride in Cats with Experimentally Induced or Spontaneously Occurring Chronic Renal Failure . J. Vet. Med. Sci . 2007 ; 69 : 1015 - 1023 . PMID: 17984588
15. Zhao Q , Yu S , Zou M , Dai Z , Wang X , Xiao J , et al. Effect of renal sympathetic denervation on the inducibility of atrial fibrillation during rapid atrial pacing . J Interv Card Electrophysiol . 2012 ; 35 : 119 - 125 . doi: 10.1007/s10840- 012 - 9717 -y PMID : 22869391
16. Fukunaga N , Takahashi N , Hagiwara S , Kume O , Fukui A , Teshima Y , et al. Establishment of a model of atrial fibrillation associated with chronic kidney disease in rats and the role of oxidative stress . Heart Rhythm . 2012 ; 9 : 2023 - 2031 . doi: 10.1016/j.hrthm. 2012 . 08.019 PMID: 22906534
17. Alonso A , Lopez FL , Matsushita K , Loehr LR , Agarwal SK , Chen LY , et al. Chronic kidney disease is associated with the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study . Circulation . 2011 ; 123 : 2946 - 2953 . doi: 10.1161/CIRCULATIONAHA.111.020982 PMID: 21646496
18. Ewen S , Ukena C , Linz D , Schmieder RE , Bohm M , Mahfoud F. The sympathetic nervous system in chronic kidney disease . Curr Hypertens Rep . 2013 ; 15 : 370 - 376 . doi: 10.1007/s11906- 013 - 0365 - 0 PMID: 23737218
19. Ye S , Zhong H , Yanamadala V , Campese VM . Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity . Am J Hypertens . 2002 ; 15 : 717 - 724 . PMID: 12160195
20. Wienemann H1 , Meincke F , Kaiser L , Heeger CH , Bergmann MW . Treating resistant hypertension with new devices . Minerva Cardioangiologica . 2014 ; 62 : 235 - 41 . PMID: 24831759
21. Ogawa M , Tan AY , Song J , Kobayashi K , Fishbein MC , Lin SF , et al. Cryoablation of stellate ganglia and atrial arrhythmia in ambulatory dogs with pacing-induced heart failure . Heart Rhythm . 2009 ; 6 : 1772 - 1779 . doi: 10.1016/j.hrthm. 2009 . 08.011 PMID: 19959128
22. Redpath CJ , Rankin AC , Kane KA , Workman AJ . Anti-adrenergic effects of endothelin on human atrial action potentials are potentially anti-arrhythmic . J Mol Cell Cardiol . 2006 ; 40 : 717 - 724 . PMID: 16603181
23. Linz D , Mahfoud F , Schotten U , Ukena C , Hohl M , Neuberger HR , et al. Renal sympathetic denervation provides ventricular rate control but does not prevent atrial electrical remodeling during atrial fibrillation . Hypertension . 2012 ; 61 : 225 - 231 . doi: 10.1161/HYPERTENSIONAHA.111.00182 PMID: 23150501
24. Bianchi S , Rossi P , Della Scala A , Kornet L , Pulvirenti R , Monari G , et al. Atrioventricular (AV) node vagal stimulation by transvenous permanent lead implantation to modulate AV node function: safety and feasibility in humans . Heart Rhythm . 2009 ; 6 : 1282 - 1286 . doi: 10.1016/j.hrthm. 2009 . 05.011 PMID: 19716083
25. Thomas H , Jeffrey E. Atrial Fibrosis and the Mechanisms of Atrial Fibrillation . Heart Rhythm . 2007 ; 4 : S24 - S27 . PMID: 17336879