CLINICAL RESEARCH
Europace (2009) 11, 1301–1307
doi:10.1093/europace/eup220
Atrial Fibrillation – clinical issues
Effects of angiotensin receptor blockade on serial
P-wave signal-averaged electrocardiograms after
electrical cardioversion of persistent
atrial fibrillation
Finn Hegbom 1*, Arnljot Tveit 2, Irene Grundvold 1, Harald Arnesen 1, and Pal Smith 2
1
Department of Cardiology, Ulleval University Hospital, 0407 Oslo, Norway; and 2Department of Internal Medicine, Asker and Baerum Hospital, 1309 Rud, Norway
Received 23 April 2009; accepted after revision 16 July 2009; online publish-ahead-of-print 6 August 2009
Aims
To evaluate the effects of the angiotensin II type 1 receptor blocker candesartan on P-wave signal-averaged electrocardiogram (P-SAECG) after electrical cardioversion in patients with atrial fibrillation (AF).
.....................................................................................................................................................................................
Methods
One hundred and seventy-one patients with persistent AF were randomized to receive candesartan 8 mg/day or
placebo for 3– 6 weeks before and candesartan 16 mg/day or placebo for 6 months after electrical cardioversion.
and results
P-SAECG was recorded in 114 patients (57 in each treatment group) after cardioversion and repeated in those
with sinus rhythm at 1 and 6 weeks, and 3 and 6 months. Filtered P-wave duration (FPD), root-mean-squared
(RMS) voltages of the terminal 40 ms of the filtered P-wave, RMS voltage of the entire filtered P-wave, and the integral of the voltages in the entire PD were analysed. No effects of candesartan were observed on any P-SAECG parameter at baseline. In the subgroup of patients in sinus rhythm after 6 months, FPD was significantly shorter both at
baseline (151 + 16 vs. 163 + 16 ms) and at 6 months (143 + 12 vs. 153 + 15 ms) in the candesartan (n ¼ 15) compared with the placebo group (n ¼ 21).
.....................................................................................................................................................................................
Conclusion
Treatment with candesartan was associated with a shorter FPD in patients remaining in sinus rhythm for 6 months.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Atrial fibrillation † Cardioversion † P-SAECG † Angiotensin blocker
Introduction
Atrial fibrillation (AF) commonly recurs in patients after electrical cardioversion. Duration of AF, increasing age, advanced underlying heart
disease, non-use of antiarrhythmic drugs, larger atria, and a prolonged
P-wave duration are predictors of recurrences of AF during
follow-up.1 The mechanisms of AF initiation and perpetuation are
not fully understood. However, over time it seems to become selfperpetuating, possibly secondary to atrial remodelling induced by
the arrhythmia itself.2 Atrial electrical remodelling is associated
with shortening of atrial refractoriness, loss of rate adaptation,
and prolongation of atrial conduction time.2 – 4 Previous reports
have demonstrated significant correlation between intra-atrial
conduction time and the duration of P-wave measured by P-wave
triggered signal-averaged electrocardiogram (P-SAECG).4 – 6 Moreover, persistence of abnormal atrial conduction detected by
P-SAECG has been able to identify patients who are at high risk of
recurrent AF following cardioversion.7
Activation of the renin-angiotensin system (RAS) has been implicated in the pathophysiology of AF, and there is increasing evidence suggesting that modulation of the RAS have a role in the
prevention of AF particularly in hypertensive and heart failure
patients.8
The present study, a substudy of CAPRAF9 (candesartan in the
prevention of relapsing atrial fibrillation), was conducted to evaluate the effects of the angiotensin II type 1 receptor blocker (ARB)
candesartan on serial P-SAECG after electrical cardioversion in
patients with persistent AF.
* Corresponding author. Tel: þ47 22119448, Fax: þ47 22119060, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: [email protected].
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Methods
The present study was a pre-specified substudy of the CAPRAF.
Briefly, this was a dual-centre, parallel, randomized, and placebocontrolled study that investigated the effects of treatment with the
ARB candesartan on the recurrence rate of AF after electrical cardioversion of persistent AF. The patients were randomized to receive
tablets of candesartan 8 mg or placebo once daily for 3 – 6 weeks
before cardioversion, depending on the time needed for warfarin
treatment to maintain an international normalized ratio of .2.2 for
a minimum of 3 weeks. No patients received any class I or III antiarrhythmic drugs.
Electrical cardioversion was performed under propofol anaesthesia.
A 12-lead ECG and a baseline P-SAECG were recorded and an echocardiographic examination was performed between 2 and 4 h after
successful cardioversion. Patients who were successfully cardioverted
received candesartan 16 mg or placebo once daily during the follow-up
period of 6 months, or until recurrence of AF was documented.
A clinical examination and a 12-lead ECG recording were preformed
at 1 and 6 weeks, 3 and 6 months after cardioversion, or at any
time if they had symptoms indicating recurrence of AF. At each visit,
a P-SAECG was recorded in patients with sinus rhythm.
All patients provided written informed consent in accordance with
the Declaration of Helsinki before enrolment. The study was approved
by the Regional Committee for Medical Research Ethics and registered
at clinicaltrials.gov.
P-wave signal-averaged electrocardiogram
recordings and analysis
Following cardioversion, a P-SAECG was recorded with a MAC VU
5000 ECG analysis system installed with PHIRES software (GE
Medical Systems, Milwaukee, WI, USA). Each patient was studied
while supine in a quiet room. The skin at the site of electrode placement was cleaned with alcohol and thereafter scrubbed with a
rubbing pad. The signal from each lead was recorded with a bandwidth
of 40– 250 Hz and converted to digital data with 16-bit accuracy at a
sampling rate of 1 kHz. At least 250 beats were recorded to achieve
a noise level,1.0 mV. The filtered signals from the Frank orthogonal
bipolar X, Y, and Z leads were combined into a vector magnitude of
the P-wave [square-root of X2 þ Y2 þ Z2)]. P-wave onset and
offset were selected automatically by the ECG analysis system. All
recordings were visually reviewed independently by two investigators
(F.H. and A.T.). P-wave onset and offset were manually edited if
required.
The following parameters from the P-SAECG analysis were studied:
(1) total filtered P-wave duration (FPD), (2) root-mean-squared (RMS)
voltages of the terminal 40 ms of the filtered P-wave (RMS-40),
(3) RMS voltage of the entire filtered P-wave (RMS-p), and (4) the
integral of the voltages in the entire PD (integral-p).
Statistical analyses
The data are presented as mean + SD for continuous variables unless
otherwise stated, and categorical data are given as counts. Comparisons between groups of normally distributed variables were performed with the two-tailed Student’s t-test for paired or unpaired
data. The Mann– Whitney U-test or Wilcoxon rank tests were used
for comparisons between groups of non-normal distribution. In
Kaplan – Meier survival analysis, the log-rank test was used to
compare the probability of freedom from AF recurrence between
treatment groups and for P-SAECG parameter quartiles. Categorical
data were compared with the x 2 or Fisher’s exact test as appropriate.
F. Hegbom et al.
Linear regression analysis with covariates (ANCOVA) was employed
to compare changes over time. A P-value of ,0.05 was considered
statistically significant. The SPSS (Statistical Package for Social Sciences
version 13.0, SPSS Inc., Chicago, IL, USA) was used for all statistical
analyses.
Results
Patient characteristics
The present study population consisted of 136 patients with 333
P-SAECG recordings. Twenty-two patients (36 recordings) were
excluded due to technical difficulties, high noise levels
(1.0 mV), adverse events, or failure to complete the follow-up.
Thus, the final study population consisted of 114 patients with
297 recordings.
Table 1 displays the characteristics at baseline of all patients and
of those who remained in sinus rhythm at 6 months. There were
no significant differences in characteristics between patients randomized to candesartan compared with placebo, neither in all
patients nor among those remaining in sinus rhythm after
6 months. The most apparent difference was between patients
receiving statins in those remaining in sinus rhythm at 6 months
(35.3% vs. 13.6% between treatment groups, P ¼ 0.142). Most
patients had preserved left ventricular (LV) function and only
mildly enlarged left atrium. Only one patient had clinical heart
failure. The duration of AF prior to cardioversion was unknown
in 50% of patients, but with no differences between treatment
groups. Out of 114 patients with a P-SAECG recording at baseline,
36 patients (31%) were in sinus rhythm at 6 months (15 patients in
the candesartan group and 21 patients in the placebo group).
Serial P-wave signal-averaged
electrocardiogram measurements
Table 2 lists the P-SAECG measurements at baseline in all patients
and in those remaining in sinus rhythm at 6 months, and at
6 months in patients remaining in sinus rhythm. Analysing all
patients, there were no significant differences in baseline measurements for any parameter when comparing the two treatment
groups. However, there was a parallel and statistically significant
decrease in FPD and integral-p between baseline and 6 weeks in
both groups (Figure 1). FPD was significantly lower at 6 months
in the candesartan compared with the placebo group (P ¼ 0.04).
There were no differences in RMS-40 or RMS-p between groups
or between visits during the 6 months follow-up.
Because of comparisons of different patient populations at different visits, those who remained in sinus rhythm at 6 months were
compared at baseline and during follow-up (Figure 2). FPD was significantly lower in the candesartan group compared with the placebo
group at baseline (P ¼ 0.03). There was a parallel and statistically significant decrease in FDP during follow-up with no differences in
changes between the groups. For the other parameters, there
were no statistically significant differences during follow-up.
Baseline FPD was strongly correlated with left atrial diameter
(r ¼ 0.334; P , 0.001), left atrial area (r ¼ 0.315; P ¼ 0.001), and
age (r ¼ 0.325; P , 0.001). Neither RMS-40, RMS-p, nor integral-P
was correlated with left atrial dimensions or age. In univariate
1303
Angiotensin receptor blockade and P-SAECG
Table 1 Baseline characteristics in all patients and in patients who remained in sinus rhythm at 6 months
All patients
.......................................................
Patients in SR at 6 months
.......................................................
Candesartan (n 5 58)
Placebo (n 5 56)
Candesartan (n 5 15)
Placebo (n 5 21)
Age (years)
64 + 9
62 + 12
65 + 10
64 + 12
Sex (woman/men)
Body mass index (kg/m2)
17/41
26 + 3
12/44
27 + 4
5/10
26 + 3
4/17
27 + 4
Hypertension (%)
24.1
32.1
29.4
36.4
Coronary heart disease (%)
8.6
10.7
11.8
13.6
Diabetes (%)
Chronic obstructive pulmonary disease (%)
6.9
1.7
7.1
3.6
5.9
5.9
0.0
0.0
Blood pressure systolic (mmHg)
Blood pressure diastolic (mmHg)
138 + 18
87 + 13
137 + 22
90 + 13
136 + 19
84 + 13
138 + 23
87 + 13
Heart rate during AF (bpm)
84 + 19
83 + 15
83 + 20
81 + 13
...............................................................................................................................................................................
Demographic data
Blood pressure and heart rate
Drugs
Digitoxin (%)
8.6
7.1
0.0
9.1
b-Blockers (%)
36.2
39.3
52.9
40.9
Calcium channel blockers
Diuretics (%)
48.3
6.9
39.3
8.9
29.4
5.9
22.7
9.1
Statins (%)
13.8
12.5
35.3
13.6
Echocardiogram
Left atrial diameter (long-axis view, mm)
45.9 + 5.5
44.8 + 5.6
44.2 + 6.5
44.4 + 6.8
Left atrial area (cm2)
26.9 + 4.7
27.2 + 4.9
26.1 + 5.0
27.4 + 5.2
Right atrial area (cm2)
End-diastolic left ventricular dimension (mm)
24.1 + 5.0
51.1 + 6.0
23.5 + 3.8
51.5 + 5.2
22.6 + 4.0
50.9 + 5.6
23.1 + 4.3
50.4 + 5.2
End-systolic left ventricular dimension (mm)
35.9 + 6.4
36.1 + 5.9
36.5 + 6.7
35.6 + 5.1
Fractional shortening (%)
30.5 + 7.3
29.3 + 7.3
30.2 + 7.1
30.0 + 5.9
Table 2 P-SAECG after electrical cardioversion at baseline in all patients and in those remaining in sinus rhythm at
6 months, and at 6 months in patients remaining in sinus rhythm
FPD (ms)
.................................
Candesartan
Placebo
RMS-40 (mV)
................................
Candesartan
Placebo
RMS-p (mV)
................................
Candesartan
Placebo
Integral-p (mV s)
..................................
Candesartan
Placebo
...............................................................................................................................................................................
Baseline
All patients
159 + 17
161 + 16
5.1 + 2.5
5.2 + 2.5
6.3 + 2.3
6.9 + 2.4
744 + 283
816 + 309
Pts. in SR 6 months
151 + 16
163 + 16*
5.4 + 3.2
4.9 + 2.3
6.7 + 2.6
7.0 + 2.7
745 + 294
814 + 305
At 6 months
Pts. in SR 6 months
143 + 12
153 + 15*
5.3 + 1.6
5.0 + 2.2
6.2 + 1.9
6.5 + 1.9
660 + 181
749 + 236
Pts., patients; SR, sinus rhythm; FPD, filtered P-wave duration; integral-p, integral of the P-wave; RMS-40, root-mean-squared voltages of the terminal 40 ms; RMS-p, the integral of
the voltages in the entire PD. Values are expressed as mean + SD.
*P-value of ,0.05 between the treatment groups.
analysis, all baseline P-SAECG variables were unaffected by the
presence of hypertension, coronary heart disease, or diabetes.
Likewise, current treatment with b-blockers, verapamil, digitoxin,
and statins had no impact on the P-SAECG parameters, except
for a slightly lower RMS-p in patients on treatment with verapamil
(5.8 + 2.2 vs. 6.9 + 2.4 mV; P ¼ 0.02) compared with those not on
this drug.
Comparing quartiles of FDP at baseline in Kaplan–Meier survival
analysis, no significant predictive value with regard to risk of recurrence of AF was found (log rank, P ¼ 0.510). However, the lowest
quartile (corresponding to FDP of ,147 ms) appeared to have a
slightly better outcome (lower risk of recurrence of AF).
However, when comparing the lowest with the three upper quartiles, the apparent difference was not found to be statistically
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F. Hegbom et al.
Figure 1 Serial P-SAECG after electrical cardioversion in patients with persistent AF. FPD, filtered P-wave duration; integral-p, integral of the
P-wave; RMS-40, root-mean-squared voltages of the terminal 40 ms; RMS-p, the integral of the voltages in the entire PD; asterisk denotes
P-value ¼ 0.04 between the groups. Values are expressed as mean + SD.
significant (Figure 3). The apparent difference occurs after a delay
of 1 week.
We also compared baseline values of FPD in those with early
recurrence of AF within 1 week (45% of patients) with the
group of patients in sinus rhythm at 6 months. There were no significant differences in FPD between the groups (161 + 17 vs.
158 + 17 ms in the two groups, respectively, P ¼ 0.32).
Effect of candesartan on recurrences
of atrial fibrillation
The results from the main CAPRAF study showed that the recurrence rate of AF during the 6 months follow-up was high (68%)
and that treatment with candesartan did not reduce the recurrence rate when compared with placebo. Similar results were
observed in the present subgroup of patients with a baseline
P-SAECG recording. Median time to recurrence of AF was 9
days in the candesartan group and 8 days in the placebo group.
In the candesartan group, 28% of the patients were in sinus
rhythm after 6 months, whereas in the placebo group, 30%
remained in sinus rhythm. Kaplan –Meier analysis showed no difference in the probability of freedom from AF during follow-up when
comparing the groups (Figure 4).
In patients included in this substudy, there was a tendency
towards more patients recurring to AF within 1 week in the
candesartan group than in the placebo group (18 vs. 9; P ¼
0.06). However, we believe this is by chance, as this pattern was
less clear in the main study including all randomized patients (21
vs. 16; P ¼ 0.311).
Discussion
Compared with placebo, treatment with candesartan prior to electrical cardioversion of AF had no impact on baseline atrial electrophysiology as evaluated by P-SAECG. FPD at 6 months was lower
in both groups compared with baseline values, and there was a significantly shorter FPD in the candesartan group compared with the
placebo group.
The decrease in FPD during follow-up is consistent with findings
from other studies,7,10 – 16 suggesting that at least some intra-atrial
conduction delay is reversible in this patient population. A prolonged P-wave duration is believed to reflect increased intra-atrial
conduction time17 and is associated with AF.7 Although P-wave
duration was not predictive of rhythm outcome after cardioversion
in our study, shorter P-wave durations after cardioversion of persistent AF have been associated with long-term maintenance of
sinus rhythm in other studies. The apparent difference in the recurrence of AF comparing the lowest with the upper three quartiles
of baseline FDP in our study is in accordance with most previous
studies.
Angiotensin receptor blockade and P-SAECG
1305
Figure 2 Serial P-SAECG after electrical cardioversion in 36 patients who remained in sinus rhythm at 6 months. FPD, filtered P-wave duration; integral-p, integral of the P-wave; RMS-40, root-mean-squared voltages of the terminal 40 ms; RMS-p, the integral of the voltages in the
entire PD; n ¼ 21 in the placebo group; n ¼ 15 in the candesartan group. Values are expressed as mean + SD. Asterisk denotes P-value , 0.05
when comparing the groups.
Figure 3 Kaplan – Meier curves showing the proportion of
patients free from AF recurrence comparing the lowest quartile
(corresponding to FPD of ,147 ms) with the upper three
quartiles of FPD. The apparent difference was not found to be
statistically significant (log rank, P ¼ 0.165). FDP, filtered P-wave
duration.
Figure 4 Kaplan– Meier curves showing the proportion of
patients free from AF recurrence in the candesartan and
placebo groups during follow-up (n ¼ 114).
1306
A small, non-randomized study demonstrated shorter FPD and
reduction in AF recurrences after electrical cardioversion in
patients using ACE-inhibitor; however, the use of b-blocker was
considerably higher in those not using ACE-inhibitor and may
have been a confounding factor.18
FPD was significantly lower in the candesartan group compared
with the placebo group 6 months after cardioversion of AF. When
comparing those who remained in sinus rhythm at 6 months, a
shorter FDP in the candesartan group was already evident at baseline compared with the placebo group. One might speculate
that in this subgroup of patients, treatment with candesartan for
3 –6 weeks before cardioversion may have affected atrial electrophysiology. This is consistent with the idea that those who
remain in sinus rhythm after cardioversion may have less irreversible structural and electrical changes in the atria. Candesartan
modulates electrical remodelling by preventing shortening of the
effective atrial refractory period during short-term rapid atrial
pacing in a dog model.19 In a long-term rapid atrial pacing model
in dogs, candesartan prevented the increase in intra-atrial conduction time observed in the control group. The mean AF duration
was significantly shorter in the candesartan group compared with
the control group.20 This is consistent with findings from some
studies showing that short atrial refractory period or prolonged
intra-atrial conduction time predicts recurrence of AF in patients
after electrical cardioversion.4
The slightly shorter FPD in the candesartan group at 6 months
did not result in reduction of AF recurrences when compared with
the placebo group. The reasons for this may be several. Almost all
patients in our study had normal LV systolic function, and 50%
had lone AF. Retrospective analyses of large trials indicate that
ACE-inhibitors and ARBs may prevent development of AF in
patients with heart failure, hypertension with LV hypertrophy,
post-cardioversion, and in post-MI patients.8 Patients included in
these trials had more severe underlying heart disease, and the
level RAS stimulation was probably markedly elevated. Moreover,
the exposure time to ARBs or ACE-inhibitors was longer. In the
present study, the relative short treatment duration and the low
drug dosage prior to cardioversion may have influenced the
results, and as one previous study has shown that a higher
dosage may result in a reduction in AF recurrences after cardioversion.21 Madrid et al.22 prospectively studied the effects of adding
irbesartan to amiodarone treatment prior to electrical cardioversion of persistent AF. Recurrences of AF were reduced in patients
receiving irbesartan. Similarly, Ueng et al.23 showed that adding
enalapril to amiodarone reduced AF recurrences after cardioversion. In these studies, it appears that ACE-inhibitor/ARBs and
amiodarone have a synergistic effect in reducing early AF
recurrences.
It is worth-mentioning that in the GISSI-AF study, a recently
large randomized, prospective study, treatment with valsartan
was not associated with a reduction in the incidence of AF.24
Study limitations
Our study has some important limitations. First, P-SAECG is not a
measure of atrial refractoriness and does not directly measure
intra-atrial conduction time. Moreover, the short treatment duration and low drug dosage prior to cardioversion may have
F. Hegbom et al.
affected the results. Our results only apply to patients with well
preserved LV systolic function and may be different in patients
with severe organic heart disease.
Conclusion
Treatment with candesartan 3 –6 weeks prior to electrical cardioversion of persistent AF did not result in any differences in baseline
atrial electrophysiology as measured by P-SAECG compared with
placebo. However, in the subgroup of patients who remained in
sinus rhythm 6 months after cardioversion, the FPD was shorter
in the candesartan group compared with the placebo group both
at baseline and during follow-up. This may have resulted from
altered atrial electrophysiology during treatment with candesartan
prior to cardioversion. Nevertheless, treatment with candesartan
did not result in a reduction of AF recurrence during follow-up.
Acknowledgements
We acknowledge the clinical research nurses Mona Olufsen and
Anne Kari Brun for patient logistics, registration, and documentation of data at Asker & Baerum Hospital and Ulleval University
Hospital.
Funding
AstraZeneca, Molndal, Sweden, provided the study medication.
Conflict of interest: none declared.
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