Introduction
Atrial fibrillation (AF) is the most common type of
cardiac arrhythmia; however, current therapies are not efficient in
the management of this condition (1). Although multiple treatment methods
exist, no single modality is effective in all patients. Pulmonary
vein isolation has emerged as an effective method for the treatment
of AF. However, recurrences are frequent and occur in 10–40% of
patients (2–4). An increasing number of clinical and
experimental studies have revealed that AF is associated with
atrial electrical and structural remodeling (5). Valsartan (recognized by the trade
name, Diovan) is an angiotensin II (Ang II) receptor antagonist,
also known as Ang II receptor blocker (ARB), which possesses a
particularly high affinity for the type I Ang II (AT1)
receptor (6). A previous study in
atrial rapid-pacing dogs has demonstrated that valsartan may
prevent the induction and promotion of AF through the attenuation
of calpain I upregulation and the suppression of atrial structural
remodeling (7). Furthermore, Ang
II has been demonstrated to be involved in the mediation of
inflammatory responses, which are also involved in the development
of AF (8). However, previous
studies on the comparative effects of the administration of
Ang-converting-enzyme inhibitor (ACEI) or ARB on the incidence of
AF have reported inconsistent findings (9–11).
Despite some studies demonstrating that ARB may not lower the
incidence of AF, further studies are required due to the multiple
biological effects of ARB. The aim of the present study was to
evaluate the efficacy of treatment with ARBs in patients undergoing
antral pulmonary vein isolation.
Materials and methods
Participants
In total, 120 randomly selected patients, referred
to the Arrhythmia Unit of the Beijing AnZhen Hospital (Beijing,
China) for AF ablation therapy between December 2008 and July 2012,
were enrolled into this study. Patients developing major
postablation complications or in which AF ablation was considered
to be unsuccessful (patients presenting permanent AF) were not
included in the analysis, due to the low possibility of late
conversion to sinus rhythm in these patients, and the effect of
renin-Ang-aldosterone system (RAAS) inhibitors in decreasing AF
could not be demonstrated. Further exclusion criteria included:
Secondary causes of hypertension; congestive heart failure with
symptoms classified as class II to IV, according to the New York
Heart Association functional classification (12); left ventricular ejection fraction
of <35%; previous coronary artery stenting or angioplasty;
previous AF ablation procedure; transverse left atrial diameter of
60 mm, detected by transthoracic echocardiography; administration
of amiodarone treatment; valvular diseases; and suffering from type
1 diabetes mellitus. This study was approved by the Medical Ethics
Committee of Beijing AnZhen Hospital. All the patients provided
informed written consent prior to participation in this study.
Study design
All the patients were randomly divided, by
computer-generated randomization, into the control (placebo), 80
mg/day valsartan or 160 mg/day valsartan (Novartis AG, Basel,
Switzerland) groups. The variables considered in this study
included: age, gender, body mass index, presence/absence of
coronary artery disease, type of AF (paroxysmal and persistent),
hypertension and diabetes mellitus. Baseline examinations were
performed prior to ablation. The patients administered ACEIs or
ARBs for the treatment of hypertension were also administered a
calcium antagonist at least four weeks before AF ablation. Three
weeks before ablation, all the patients were administered the
anticoagulant, warfarin (target international normalized ratio,
2.0–3.0; Shanghai Xinyi Pharmaceutical Co., Ltd., Shanghai, China),
unless contraindicated. Patients free from AF were further
adminsitered warfarin three months after ablation. Subsequently,
the patients were subjected to pulmonary vein isolation and were
administered valsartan. The valsartan dose of 160 mg/day was
reached by administration in two stages, lasting one week each; the
patients were admininstered 80 mg/day in the first week, and 160
mg/day in the next week. For all the patients, follow-up was
performed for at least one year after ablation. The initial three
months after AF ablation were considered to be the ‘blanking
period’, during which AF recurrence was not considered as an
indicator of ablation failure. The patients were examined each
month within the first 3 months, followed by examination at six and
twelve months after AF ablation, as well as on any other occasions
when the patients presented symptoms. A 24-h Holter recording was
performed at one, six and twelve months after ablation, in order to
monitor the electrocardiograms of the patients. Prior to AF
ablation, all the patients were subjected to delayed enhancement
cardiac magnetic resonance imaging to determine the extent of
atrial fibrosis (13). In order to
determine the extent of myocardial fibrosis, the patients received
intravenous gadolinium (0.1 mmol/kg body weight;
MultiHance®; Bracco Diagnostics Inc., Princeton, NJ,
USA).
Outcome measurements
The present study compared the administration of 80
mg/day valsartan, 160 mg/day valsartan and a placebo to assess the
efficacy of different doses of valsartan based on the cumulative
number of patients relapsing into AF following ablation to maintain
the sinus rhythm. The primary endpoint was failure of the AF
treatment during the follow-up. The beginning of the follow-up
period for this purpose was considered to be the day of the
ablation. A blanking period of three months was used after
ablation, and recurrences within the first three months were not
classified as failure of the ablation. Any patient suffering a
persistent atrial arrhythmia during this period was reverted to
sinus rhythm by electrical cardioversion.
Statistical analysis
Statistical analysis was performed using the SPSS
software (version 13.0; SPSS, Inc., Chicago, IL, USA). The results
are expressed as the mean ± standard deviation. Categorical
variables were compared by χ2 analysis, while continuous
variables were compared by Student’s t-test. Kaplan-Meier analysis
was performed to determine the probability of treatment success,
which was expressed as the percentage of patients remaining free
from AF. Differences in arrhythmia-free survival were assessed with
the log-rank test. The recurrence of AF was analyzed using the Cox
proportional-hazards regression, to regulate potentially
confounding factors. P<0.05 was considered to indicate a
statistically significant difference.
Results
In total, 120 patients were included in the
analysis. A total of 40 patients were randomly selected for
treatment with a placebo, while 40 patients were treated with 80
mg/day valsartan and 40 patients were treated with 160 mg/day
valsartan. The baseline clinical characteristics (prior to
ablation) of each group are shown in Table I. No statistically significant
differences were observed in all the pre-treatment characteristics
among the three treatment groups. The median duration of AF prior
to randomization was 8.6±7.2, 9.7±8.2 and 9.1±7.8 months in the 80
mg/day valsartan, 160 mg/day valsartan and placebo groups,
respectively, with no statistically significant differences
observed among the three groups. No patients succumbed to the
disease or were not able to follow-up during the study.
 | Table IMain demographic, clinical and
echographic characteristics of patients in the three treatment
groups. |
Table I
Main demographic, clinical and
echographic characteristics of patients in the three treatment
groups.
| Variable | Control (n=40) | 80 mg/day valsartan
(n=40) | 160 mg/day valsartan
(n=40) |
|---|
| Age, years | 63.4±8.5 | 62.5±8.1 | 63.7±9.2 |
| Male gender, n
(%) | 18 (45.0%) | 17 (42.5) | 22 (55.0) |
| Weight, kg | 75.3±14.1 | 74.3±12.9 | 78.2±15.3 |
| SBP, mmHg | 135.6±19.3 | 136.6±20.1 | 135.8±18.7 |
| DBP, mmHg | 76.3±11.2 | 80.1±12.8 | 79.6±11.6 |
| TC, mg/dl | 187.3±13.2 | 179.5±11.8 | 189.5±14.2 |
| HDL-C, mg/dl | 34.6±5.2 | 38.7±5.3 | 33.5±4.8 |
| FPG, mg/dl | 106.2±10.0 | 110.7±11.1 | 109.7±10.8 |
| HR, beats/min | 76.2±12.1 | 72.7±10.1 | 77.9±13.1 |
| AF duration,
months | 8.6±7.2 | 9.7±8.2 | 9.1±7.8 |
| Episodes of AF,
n | 2.6±0.7 | 2.4±0.6 | 2.7±0.9 |
| Ejection fraction,
% | 61.0±8.2 | 60.8±8.2 | 60.1±7.9 |
| Pre-ablation atrial
fibrosis, n | 17.2±11.8 | 17.8±12.0 | 17.3±11.8 |
| BMI | 23.6±2.4 | 24.1±2.5 | 23.8±2.4 |
| Presence of CAD
(n) | 7 (17.5) | 8 (20) | 8 (20) |
| Type of AF, n
(%) |
| Paroxysmal | 33 (82.5) | 32 (80) | 30 (75) |
| Persistent | 7 (17.5) | 8 (20) | 10 (25) |
Following the completion of a mean follow-up period
of 12.1±9.6 months, 92 patients were found to be free from AF
(Table II). At the end of the
follow-up period, 21/40 patients treated with 80 mg/day valsartan,
38/40 patients treated with 160 mg/day valsartan and 18/40 patients
treated with a placebo were found to be free of AF. The systolic
blood pressure (SBP) and diastolic blood pressure (DBP) at the end
of the follow-up period were significantly different in patients
treated with 80 mg/day (SBP, 114±19 mmHg; DBP, 72±11 mmHg DBP) and
160 mg/day valsartan (SBP, 125±10 mmHg; DBP, 71±8 mmHg) valsartan,
when compared with the control patients (SBP, 130±15 mmHg; DBP,
78±13 mmHg). Univariate analysis identified that P=0.3 for SBP and
P=0.03 for DBP.
| Table IIResults of the intention-to-treat
analysis. |
Table II
Results of the intention-to-treat
analysis.
| Variable | Control (n=40) | 80 mg/day valsartan
(n=40) | 160 mg/day valsartan
(n=40) |
|---|
| Sinus rhythm (three
months after ablation), n | 26 | 30 | 38 |
| Sinus rhythm (end of
follow-up), n | 18 | 21 | 36 |
| Systolic blood
pressure (end of follow-up), mmHg | 125±10 | 130±15 | 114±19 |
| Diastolic blood
pressure (end of follow-up), mmHg | 71±8 | 78±13 | 72±11 |
| Mortality rate (end
of follow-up), n | 0 | 0 | 0 |
Kaplan-Meier analysis demonstrated that the 12-week
probability for maintaining sinus rhythm was 92% in patients
receiving 160 mg/day valsartan, whereas the probability was 76% in
patients receiving 80 mg/day valsartan and 67% in patients
receiving placebo treatment (P<0.05). The Kaplan-Meier analysis
of the time until the first recurrence during the follow-up period
revealed that patients treated with 160 mg/day valsartan presented
a greater probability of remaining free of AF (88% in the 160
mg/day valsartan group, vs. 65% in the 80 mg/day valsartan group
and 47% in the placebo group; Fig.
1). Treatment with 80 mg/day valsartan was not found to
decrease the recurrence rate of AF when compared with the control
group (P=0.07). No statistically significant difference was
observed between the 80 and 160 mg/day valsartan doses (P=0.06),
whereas the difference between the 160 mg/day valsartan and control
groups was statistically significant (P=0.01).
Multivariate analysis revealed that the use of 160
mg/day valsartan was the only significant variable associated with
the maintenance of sinus rhythm following ablation. The Cox
proportional model was used to correct for different variables
(including age, gender, AF duration, left atrium size, SBP and
DBP), which may influence the results. Treatment with 160 mg/day
valsartan was found to be associated with a lower risk of AF
recurrence (hazard ratio, 0.46; 95% confidence interval, 0.20–0.93;
P=0.01).
Discussion
A randomized trial was performed in the present
study, comparing the effect of two doses of valsartan (80 and 160
mg/day) on the recurrence rate of AF following ablation in 120
patients. The results indicated that the recurrence rate of AF was
affected in a dose-dependent manner and was lower in the group
treated with 160 mg/day valsartan.
Atrial fibrillation (AF) is the most common
sustained arrhythmia in clinical practice (14). Catheter ablation has emerged as an
effective therapy for AF that does not respond to other medical
treatments (15). However,
catheter ablation is limited by significant recurrence rates of
10–40%, depending on various factors, including left atrial size,
presence of persistent AF, scarring in the left atrium and AF
duration (15–17). These variables are associated with
the remodeling process, which may help trigger and maintain AF
(18). Electrical and structural
remodeling have been previously demonstrated to be associated with
inflammation and oxidative stress (19).
The progression of atrial alteration is a
fundamental component of AF pathophysiology. The RAAS is directly
and indirectly involved in the development of the AF substrate
(20,21). Previous animal studies have
demonstrated that inhibition of RAAS may prevent AF (22,23).
Furthermore, antagonists of the RAAS may have an antifibrotic
effect, due to their ability to decrease the synthesis of collagen
type I molecules, as well as increase the degradation of collagen
type I fibres (24). A previous
study has demonstrated that a blockade of the AT1
receptor reduces the development of atrial fibrosis and, thus,
chronic structural remodelling (9). Although the precise signaling
pathways resulting in atrial fibrosis remain unclear, evidence
indicates that activation of the RAAS may result in atrial
fibrosis. A number of studies have identified a positive
interaction between ARBs and potassium channel blockers on
transmembrane action potentials and currents (25,26).
In addition, ARBs have been demonstrated to modify the cardiac
delayed rectifiers, hKv1.5, HERG and Ks currents, indicating that
ARBs may possess antiarrhythmic properties.
Valsartan is a potential drug for the treatment of
hypertension, congestive heart failure or myocardial infarction
(27). A study by Li et al
demonstrated for the first time that valsartan may prevent the
induction and promotion of AF, through the attenuation of calpain I
upregulation and suppression of atrial structural remodeling in
atrial rapid-pacing dogs (7). In
addition, Harada et al identified that the transient
receptor potential canonical type-3 (TRPC3) channel plays a
critical role in AF-promoting fibroblast pathophysiology, which is
a novel potential therapeutic target (28). Furthermore, valsartan may affect
the fibrotic process by inhibiting TRPC3, which has been found to
be significantly upregulated in the atrium of canines suffering
from AF (29).
In the present study, treatment with 160 mg/day
valsartan resulted in a significantly reduced AF recurrence rate,
when compared with the control or 80 mg/day valsartan groups, which
is in agreement with the observations of previous studies (30,31).
For instance, Parving et al demonstrated the dose-dependent
effect of irbesartan in the prevention of diabetic nephropathy
(30). In addition, Madrid et
al reported that the treatment combination of irbesartan and
amiodarone decreased the rate of AF recurrences in lone AF
patients, in a dose-dependent manner (31).
In patients suffering from paroxysmal or persistent
AF, treatment with 160 mg/day valsartan following AF ablation was
found to be more effective in reducing the AF recurrence rate, when
compared with the administration of 80 mg/day valsartan. These
results indicated that the antiarrhythmic effect of valsartan may
be associated with atrial structural remodeling, as well as
specific and selective electric remodeling through the improvement
of atrial conduction disturbances. In conclusion, treatment with
160 mg/day valsartan markedly reduced the risk of AF recurrence in
a dose-dependent manner.
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