1. health and fitness
2. therapy

Clinical research
European Heart Journal (2007) 28, 1351–1357
doi:10.1093/eurheartj/ehl544
Arrhythmia/electrophysiology
Maintenance of sinus rhythm with metoprolol CR
initiated before cardioversion and repeated
cardioversion of atrial fibrillation: a randomized
double-blind placebo-controlled study
˚rdh*, Ma
˚rten Rosenqvist, Rolf Nordlander†, and Mats Frick
Anna K Nerga
Department of Cardiology, Karolinska Institutet at Stockholm South Hospital, Stockholm S-118 83, Sweden
Received 14 July 2006; revised 18 December 2006; accepted 25 January 2007; online publish-ahead-of-print 28 February 2007
KEYWORDS
Atrial fibrillation;
Cardioversion;
Metoprolol;
Arrhythmias
Introduction
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the population, and its prevalence increases with
age.1 AF may cause disabling symptoms as well as an
increased risk of tromboembolic events.2 Current recommendations concerning rate or rhythm control of AF
mainly depend on patient symptoms. Exercise capacity is
significantly reduced by chronic AF when compared with
sinus rhythm (SR), and restoration and maintenance of SR
often are important therapeutic goals for symptomatic
reasons.3 However, even with the use of class I and III antiarrhythmic drugs, the recurrence rate of AF after direct
current (DC) cardioversion is 50% after 6 months.4,5 Due
to their adverse effects and risk of pro-arrhythmias, treatment with antiarrhythmic drugs of class I and III is not generally advised in patients scheduled for their first DC
cardioversion.6 Present evidence for using b-blockers in
order to reduce relapse into AF is limited and b-blockers
are generally assumed to be less effective for this
* Corresponding author. Tel: þ46 8616 30 88; fax: þ46 8616 30 40.
†
E-mail address: anna.nergardh@sodersjukhuset.se
Deceased 3 June 2006.
purpose.7,8 However, in the previous study from our department, the use of b-blockers as well as a short duration of AF
were found to be independent predictors for maintenance of
SR.9 The highest incidence of recurrence of AF is observed
during the first weeks after cardioversion, particularly
within the first week.10 One explanation for these early
relapses is remodelling of the atria, where AF causes progressive structural and electrophysiological changes.11–14 A
strategy of repeated cardioversions without changes in
drug therapy in patients with early relapse has been evaluated and showed positive results, however without prespecified time to second cardioversion.15 The high incidence
of relapse into AF after restoration of SR in combination with
the pro-arrhythmic risks with more effective antiarrhythmic
drugs clearly show a need for evaluating more potent strategies without pro-arrhythmic side effects.
We have conducted a placebo-controlled, randomized,
double-blind trial in patients with first time persistent AF
to test the hypothesis that metoprolol controlled release
(CR) initiated at least 1 week before cardioversion, in combination with prompt repeat cardioversion in the case of
early relapse is effective in maintaining SR after DC
cardioversion.
& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
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Aims To assess the effect of metoprolol in combination with repeated cardioversion on maintenance of
sinus rhythm (SR).
Methods and results Consecutive outpatients with persistent atrial fibrillation (AF) were randomized to
treatment with metoprolol CR or placebo in a double-blind fashion. Study treatment was started at least
one week before direct current (DC) cardioversion. Patients were followed once a week during the first 6
weeks after cardioversion. In case of relapse during this period, a second cardioversion was performed.
Total treatment time was 6 months. A total of 168 patients were randomized to metoprolol (n ¼ 83) or
placebo (n ¼ 85). The dose of study treatment at cardioversion was 169 + 47 mg in the metoprolol group
and 180 + 40 mg in the placebo group (P ¼ 0.12). In an intention-to-treat analysis, 46 patients (55%) in
the metoprolol group and 34 patients (40%) in the placebo group (P ¼ 0.04) had SR 1 week after cardioversion, and 38 patients (46%) in the metoprolol group compared with 22 patients (26%) in the
placebo group had SR after 6 months (P , 0.01).
Conclusion A treatment strategy of metoprolol CR started before cardioversion in combination with
prompt second cardioversion in case of early relapse (1–6 weeks) significantly increases the proportion
of patients in SR during six months of follow-up.
1352
Methods
Consecutive patients referred to the Cardiology Department of
South Hospital in Stockholm with symptomatic persistent AF with
duration of up to 1 year and with no history of earlier DC cardioversion were eligible. In this study, persistent AF was defined as AF in
repeated ECG recordings prior to referral, and confirmed with a
24 h Holter recording prior to inclusion in all patients. Major exclusion criteria were: contraindications to treatment with betablocking agents, i.e. a history of AV-block II/III, sick sinus syndrome
or asthma, and poorly controlled congestive heart failure,
untreated thyroid dysfunction, cardiac surgery within the previous
two months as well as absolute indications for b-blocker treatment
such as known coronary artery disease (CAD). Treatment with any
class I or III anti-arrhythmic drug or calcium channel blockers such
as verapamil was also considered as an exclusion criterion. A complete medical history, physical examination, ECG and an examination of the medical notes including a review of available ECG
recordings were performed in all patients in an attempt to determine the duration of AF. All patients underwent transthoracic echocardiography prior to inclusion. All patients were treated with
warfarin, INR at levels between 2.1 and 3.0, for at least 3 weeks
before and 6 weeks after cardioversion. In total, 615 patients
were screened for inclusion. The most common reasons for not
entering the study was unwillingness to participate, absolute indication for beta-blocking treatment, and AF shown to be paroxysmal.
Study treatment
to the number of patients in SR 6 months following the first DC cardioversion. Secondary objectives were to compare the effects of
metoprolol CR and placebo on the number of patients showing
early re-initiation of AF (ERAF) after cardioversion, the number of
patients in SR at 6 weeks, the ventricular rates in patients with
relapse of AF, and to assess the tolerability of metoprolol CR.
Statistical analysis
The power calculation for the primary endpoint, namely SR 6
months after DC cardioversion, indicated that 74 patients per
group were needed. This power calculation (80% power, a ¼ 0.05,
two-sided) was made on the assumption that 25% of patients in
placebo group would have SR 6 months after DC cardioversion. We
assumed a success rate at DC cardioversion of 90%, and included a
total of 168 patients. For the primary endpoint, data were
compared using the Pearson’s x2 test. Patients were included
in the statistical analysis according to the intention-to-treat
approach. Cumulative incidence was compared using the log-rank
test.
Continuous variables are given as mean + SD values. The unpaired
t-test was used for analysis of statistical differences in variables
between the groups. In comparisons of two proportions Pearson’s
x2 test was used, and in the case of small numbers Fisher’s exact
test analysis was performed. A P-value ,0.05 was considered statistically significant. Calculations were performed with the statistical
computer package STATISTICA 7.0 (StatSoft Inc.,Tulsa, Oklahoma).
Ethics
This study was approved by the Ethics Committee of Karolinska Institute, and all patients gave their informed consent to participate.
The study was initiated by the investigators, and Astra-Zeneca,
Sweden, had no involvement in the collection, analysis, or
interpretation of data, in writing the report or in the decision to
submit the paper for publication. The design, conduction, and
interpretation of the study were undertaken by the authors. The
authors had full access to the data and take responsibility for its
integrity. All authors have read and agree to the manuscript as
written.
Cardioversion
Results
DC cardioversion was performed on an elective basis according to
standard clinical practice. Light general anaesthesia was induced
with intravenous propofol. Paddles were placed in the right
second intercostal space and in a left-sided lateral position along
the mid-axillary line. Delivery of biphasic waveform shocks was
started with 120 J and if unsuccessful followed by at least two
attempts at 200 J. Selective b1-blockers were given intravenously
to patients with rapid ventricular rates or high blood pressure.
Patients were observed 2 h following cardioversion. A pre-discharge
12-lead ECG was obtained for 2 h after cardioversion.
Patient characteristics
Follow-up
Patients were followed on an outpatient basis and were seen once a
week during the first 6 weeks following DC cardioversion. At each
visit, a 12-lead ECG was obtained. The patients were also instructed
to contact the hospital in case of symptoms indicating recurrence of
AF between the scheduled visits. If relapse was diagnosed during the
first 6 weeks after DC cardioversion, the patients were scheduled for
repeat cardioversion within 7 days, without any change in study
treatment. These patients re-entered the once-a-week visit
scheme. After the first 6 weeks, the patients had scheduled visits
three and six months after DC cardioversion. At each visit, a
resting ECG was obtained.
The primary endpoint of the study was to assess the efficacy of
metoprolol CR compared with placebo in combination with prompt
repetition of cardioversion in case of early relapse, with respect
A total of 168 patients were included in the study (Figure 1).
Eighty-three patients were randomized to treatment with
metoprolol and 85 patients to placebo. The two treatment
groups were similar with respect to all pre-treatment characteristics (Table 1). Before scheduled DC cardioversion, four
patients in the metoprolol group and four patients in the
placebo group discontinued treatment (Figure 1). In the
metoprolol group, one patient developed bradycardia
,40 beats/min, and one patient died after a cerebral haemorrhage. Two patients chose to discontinue treatment for
personal reasons. In the placebo group, four patients
chose to discontinue treatment for personal reasons.
Cardioversion
Seventy-nine patients in the metoprolol group and 81
patients in the placebo group underwent DC cardioversion.
Mean dose of study treatment (+SD) at the time of cardioversion was 169 + 47 mg in the metoprolol group compared
with 180 + 40 mg in the placebo group (P ¼ 0.12). Mean duration treatment time before cardioversion was 29.1 + 16
and 26.3 + 15 days (P ¼ 0.26) in metoprolol and placebo
groups, respectively. Fifty patients (60%) in the metoprolol
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At the time of inclusion at least 7 days prior to cardioversion,
patients were randomized to either metoprolol CR or placebo. The
metoprolol CR tablets (100 mg) and matching placebo were manufactured, packed, labeled, and distributed by AstraZeneca RD,
Mo
¨lndal, Sweden. Patients were allocated treatment according to
a computer-generated randomization list. The placebo tablets
were identical in size, weight, colour, and taste to the metoprolol
CR tablets. Tablets were packed in bottles for each patient. Compliance with the study medication was checked by pill counts. Initial
dose was 50 mg of metoprolol or placebo given once daily, with
50 mg stepwise increase to a target dose of 200 mg once daily.
A.K. Nerga
˚rdh et al.
Effects of metoprolol on maintenance of SR
Figure 1
1353
Flow diagram of the study. AE: Non-serious adverse event; SAE: Serious adverse event.
Table 1 Baseline clinical characteristics
Metoprolol
(n ¼ 83)
Placebo
(n ¼ 85)
P-value
58 (70)
68.2 + 10.1
5.3 + 2.9
13 (22)
34 (41)
4
61 (72)
66.5 + 12.2
5.1 + 2.8
19 (31)
41 (48)
3
0.79
0.32
0.65
0.27
0.34
0.68
5 (6)
7 (8)
8 (9)
5 (6)
5 (6)
4 (5)
0.97
0.52
0.21
11 (13)
35 (42)
30 (36)
27 (33)
15 (18)
43 (50)
33 (39)
30 (35)
0.43
0.27
0.72
0.71
7 (8)
44.8 + 5.9
48.9 + 5.5
10 (12)
6 (7)
7 (8)
45.2 + 5.2
49.5 + 5.8
9 (11)
5 (6)
0.96
0.63
0.55
0.76
0.72
48.6 + 7.9
49.7 + 6.7
0.35
Values are expressed as mean (+SD) or number (%) of patients.
a
Defined as the absence of any of the above mentioned diseases and
age under 60 years.
b
Four patients with aortic regurgitation, 1 patient with aortic stenosism, and 7 patients with tricuspid insufficiency. COPD, Chronic obstructive pulmonary disease; LA, left atrium; RA, right atrium; LVED, end
diastolic diameter.
and 61 patients (72%) in the placebo groups reached the
target dose of 200 mg, as shown in Table 2.
Four patients in the metoprolol group (5%) and six patients
(7%) in the placebo group never restored SR at DC cardioversion (Figure 1). One of the patients in the metoprolol group
developed bradycardia after cardioversion, and was given
atropine intravenously. This patient was later treated with
permanent pacemaker. In the metoprolol group, 11 patients
50 mg
100 mg
150 mg
200 mg
Metoprolol
Placebo
4 (5)
9 (11)
16 (19)
50 (60)
4 (5)
5 (6)
11 (13)
61 (72)
Number of patients (%).
(13%) received an intravenous b-blocker (metoprolol) at the
time of cardioversion because of rapid ventricular rates or
high blood pressures, compared to 27 patients (32%) in the
placebo group (P , 0.01).
Early relapse and repeated cardioversion
No patients in the metoprolol group showed ERAF, defined as
relapse into AF prior to the discharge ECG 2 h after cardioversion. By contrast, seven patients in the placebo group
showed ERAF (P , 0.01), five of whom had been given intravenous b-blocker treatment at time of cardioversion. Forty
patients (47%) in the placebo group and 41 patients (49%)
in the metoprolol group had a second DC cardioversion,
i.e. relapsed during the first 6 weeks after their initial DC
cardioversion (P ¼ 0.8), as shown in Figure 1. The median
duration from the detected relapse in AF until the second
cardioversion was 1 (range 0–7) and 2 (range 0–7) days in
the metoprolol and in the placebo groups, respectively.
Ten patients were subjected to their second cardioversion
after more than 7 days (10–26 days), because of nontherapeutic INR values. Nine of these patients were
treated with metoprolol and two with placebo. At this
second cardioversion, two patients developed ERAF, one
treated with metoprolol and one with placebo.
Primary endpoint, effect of study treatment
An intention-to-treat analysis of all patients with a first successful cardioversion shows that 6 months after primary DC
cardioversion, 22 patients (26%) in the placebo group and
38 patients (46%) in the metoprolol group were in SR
(P , 0.01, Table 3). The difference in proportion of patients
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Male
Age (year)
AF duration (months)
AF, unknown duration
Hypertension
Ischaemic heart
disease
COPD
Diabetes mellitus
Corrected thyroid
disease
Lone AFa
Digoxin
Diuretics
ACE-inhibitor and
AT2-inhibitors
Statin
LA dimension (mm)
LVED (mm)
Mitral regurgitation
Other significant
valvular heart
diseaseb
EF (%)
Table 2 Doses of metoprolol/placebo
1354
A.K. Nerga
˚rdh et al.
b-blockers and prevention of AF
Table 3 Number of patients in SR during follow-up
1 week
6 weeks
12 weeks
24 weeks
Metoprolol (n ¼ 83)
Placebo (n ¼ 85)
P-value
46 (55)
42 (51)
39 (47)
38 (46)
34 (40)
28 (33)
24 (28)
22 (26)
0.04
0.02
0.01
,0.01
Values expressed as number of patients (%).
Atrial remodelling and repeated cardioversion
Effect on heart rate
Mean heart rate (+SD) at time for the first cardioversion
was 76.1 beats/min (+13) and 88.2 (+14) in the metoprolol group and the placebo group, respectively (P , 0.01).
Mean heart rate (+SD) at relapse was 86.4 (+17) beats/
min in the metoprolol treatment group compared with 97.9
(+22) beats/min in the placebo group (P ¼ 0.02).
Safety and tolerability of treatment
Withdrawals from the study were seen in two patients in the
metoprolol group because of serious adverse event and
adverse event (one with hemorrhagic stroke 2 days after
initiation of anticoagulation treatment and one with
AV-block II, Figure 1). A side effect was registered if
observed on at least at one occasion and occurring in two
or more patients. Side effects were registered at each
follow-up visit 1 week, 6 weeks, 3 months, and 6 months
after primary DC cardioversion. The results of these
reports are shown in Table 4. The number of patients
included in the safety analysis was 166 patients, i.e. all
patients who received at least one dose of study drug.
Discussion
The main result of our study is that metoprolol CR in combination with prompt recardioversion in the case of early
relapse significantly increases the proportion of patients in
SR 6 months after primary DC cardioversion of persistent
symptomatic AF.
The rational for repeated cardioversion in the case of
relapse is that the duration of AF has previously been
described as an independent predictor for maintenance of
SR.9 Persistent AF is known to cause electrophysiological
changes in the atrial myocardium, which are thought to
explain the progressive nature of the arrhythmia.11 The
main mechanism for early relapses is thought to be atrial
remodelling, and in particular perturbation in atrial electrophysiological properties, i.e. atrial electrical remodelling.10–14 In a investigation by Bertaglia et al.,15 a regime
of repeated cardioversion (within 2–60 days after relapse
in AF) was useful in achieving SR after 12 months in patients
treated with class IC or III anti-arrhythmic drugs. However,
as the authors point out, it has previously been demonstrated that in patients with persistent AF recovery from
atrial electrical remodelling ranged from 12 to 72 h,20,21
and a positive effect of repeated cardioversion cannot
therefore be solely explained by the prevention of atrial
electrical remodelling. In our study, we found that patients
in the placebo group who had relapsed into AF during the
first 6 weeks and received prompt repeated cardioversion
showed significantly higher rates of relapse to persistent
AF during follow-up compared with patients who received
metoprolol treatment. This is consistent with a trial by
Fynn et al.,22 which demonstrated that early repeated
internal cardioversion (within 35 h) in the case of recurrence
of AF was of very limited value in patients without antiarrhythmic treatment.
Combination strategy
In our study, 46% of the patients in the metoprolol group
compared with 26% in the placebo group were in SR 6
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in SR between the two study groups was significant along
1 week after primary cardioversion, and remained highly
significant through out the follow-up period (Table 3). In
patients who converted to SR at the first DC cardioversion,
a log-rank test of equality over treatment groups regarding
time to second relapse during first 6 weeks after primary
DC or first relapse more than 6 weeks after primary DC
cardioversion yielded a P-value ¼ 0.02 (Figure 2).
In patients who underwent one DC cardioversion during
the study period (i.e. no relapse during the first 6 weeks
after cardioversion), 28 out of 42 (67%) patients in the metoprolol group maintained SR at 6 months follow-up, compared
with 19 out of 45 patients (42%) in the placebo group (P ¼
0.02). In patients who had a second DC cardioversion, 10
out of 41 patients (24%) in the metoprolol group and three
out of 40 patients (8%) in the placebo group showed SR 6
months after their initial cardioversion (P ¼ 0.03).
The mechanism by which a b-blocker might prevent relapse
into AF remains unexplained. There is evidence from experimental observations that stimulation of adrenorececeptors
facilitates both the induction and perpetuation of AF.16–18
Earlier studies comparing b-blockers with sotalol have
shown equality concerning prevention of relapse into
AF.7,19 However, in the study by Plewan et al.7 the dose of
sotalol was relatively low (160 mg/day), and since the
class III anti-arrhythmic effect is less pronounced at low
doses, this investigation may be interpreted as a comparisons between two b-blockers. In a placebo-controlled multicentre trial by Ku
¨hlkamp et al.,8 metoprolol showed a
significant decrease in relapse of AF after DC cardioversion
according to a log-rank test. However, the proportion of
patients in SR at 6 months differed only modest between
the treatment groups. In that investigation, the treatment
with b-blocker was started after DC cardioversion and the
dose of metoprolol might have been suboptimal. Since
relapse into AF is the most frequent during the first weeks
after DC cardioversion,9,10 our results emphasize the importance of starting treatment with b-blockers prior to DC
cardioversion in order to inhibit early relapse into AF. Moreover, it is possible that the use of a higher dose of b-blocker
in our study compared to the doses used in the study by
Ku
¨hlkamp et al.8 might have produced a more pronounced
antiarrhythmic effect.
Effects of metoprolol on maintenance of SR
1355
Table 4 Most common adverse effects (occurring for two or more
patients)
Metoprolol
(n ¼ 83)
Bradycardia
,40 b.p.m.
Fatigue
Headache
Cold hands and feet
Nausea
Sleep disturbance
Dyspnea
(aggravated)
Nightmares
Vertigo/dizziness
Abdominal pain,
diarrhoea
Chest pain
(aggravated)
Reduced physical
fitness
2
Placebo
(n ¼ 85)
P-value
0
0.15
27 (33)
10 (12)
20 (24)
7 (8)
11 (13)
19 (23)
19 (22)
10 (12)
10 (12)
3 (4)
15 (18)
11 (13)
0.14
0.95
0.04
0.18
0.43
0.09
6 (7)
8 (10)
5 (6)
8 (9)
8 (9)
4 (5)
0.61
0.96
0.70
4 (5)
2 (2)
0.39
5 (6)
1 (1)
0.09
Number (%) of patients by the most common adverse effects (occurring
for two or more patients). The number of patients included in the safety
analysis is not the same as that included in the efficacy analyses. The
safety population includes 166 patients, and is defined as all patients who
received at least one dose of study drug. Numbers in parentheses refer to %.
months after DC cardioversion using a strategy including
pre-treatment with a b-blocker and prompt repeated cardioversion in the case of early relapse. The beneficial effect of
b-blockers seems to be related partly to inhibition of AF for
the first 2 h after cardioversion (ERAF) but also to the
inhibition of subacute relapse into AF. The finding that pretreatment with b-blockers significantly reduced the incidence of ERAF is in accordance with earlier studies
showing a reduction of early relapses in AF in subgroups of
patients with b-blockers and also with verapamiltreatment,23–25 thought to be partly due to restoration of
abnormal intracellular calcium handling.12,26 However, our
finding on ERAF also could be due to few patients, and
more studies in this area are of need. There is a trend also
in our study towards that patients with hypertension had
more beneficial effect of b-blocking treatment, however
our material is too small for a significant result. In our
study, the incidence of relapse after a second cardioversion
was significantly lower in patients with b-blocker treatment.
One possible explanation is that on-going treatment with
b-blockers at the time for relapse might postpone electrical
remodelling and thereby increase the chance of remaining in
SR after the second cardioversion.
The results in our investigation regarding the proportion
of patients in SR 6 months after DC cardioversion are comparable with earlier studies using class I and III antiarrhythmic drugs as prophylactic treatment.4,5 These
drugs, however, bear a substantial risk of pro-arrhythmic
side effects.27,28 In our study, metoprolol, a b-blocker, was
well tolerated and safe for the patients even in higher
doses. Withdrawal of treatment, even because of bradycardia, was seen only in a few patients. If so, this was seen
when starting treatment, and only in one case revealed at
time for cardioversion.
Our results favour this treatment strategy for patients
with first time persistent symptomatic AF, with a proportion
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Figure 2 Cumulative number of patients in SR, subdivided by treatment group. The log-rank test of equality over treatment groups included a total number of
patients ¼ 143, metoprolol ¼ 75 and placebo ¼ 68; i.e. all patients with successful primary DC cardioversion.
1356
of patients in SR 6 months after DC cardioversion comparable with previous strategies but without a risk of
drug-induced arrhythmias. This might be even more relevant
in patient with ischaemic heart disease or congestive heart
failure in whom b-blockers have recognized beneficial
properties. Using the strategy presented in this study, it
might be possible to decrease the use of class I and III
anti-arrhythmic drugs thereby avoiding potential risks for
pro-arrhythmias.
Study limitation
Some limitations with the present study should be
noted. Our results cannot be applied to all patients with
persistent AF, since earlier cardioversion was an exclusion
criterion.
Another limitation is that our study protocol does not
allow us to state which part of the treatment, b-blocker
or prompt repeated cardioversion, is the isolated most
effective. After cardioversion, the patients were followed
once a week with 12 lead ECG. Episodes of asymptomatic
AF are known to be common, and an alternative method
could have been transtelephonic monitoring.
A.K. Nerga
˚rdh et al.
7.
8.
9.
10.
11.
12.
13.
Conclusion
Acknowledgements
We thank Ms Rigmor Ha
¨rde
´n for skilled technical assistance. We
express our gratitude to Associate Professor Andreas Sjo
¨gren for
constructive criticism of the manuscript. This study was supported
by a grant from the Swedish Heart and Lung Foundation and an
unrestricted grant from Astra-Zeneca, Sweden.
14.
15.
16.
17.
18.
19.
Conflict of interest: M.R. has received reimbursement from
Astra Zeneca as a national coordinator in clinical trials and
for lecturing. He has also received research grants from
Astra Zeneca.
References
1. Kannel WB, Abbott RD, Savage DD, Mc Namara PM. Epidemiological features of chronic atrial fibrillation: the Framingham study. N Engl J Med
1982;306:1018–1022.
2. Kalman JM, Tonkin AM. Atrial fibrillation: epidemiology and the risk and
prevention of stroke. Pacing Clin Electrophysiol 1992;15:1332–1346.
3. Lipkin DP, Frenneaux M, Stewart R, Joshi J, Lowe T, McKenna WJ. Delayed
improvement in exercise capacity after cardioversion of atrial fibrillation
to sinus rhythm. Br Heart J 1988;59:572–577.
4. Reimold SC, Cantillon CO, Friedman PL, Antman EM. Propafenone versus
sotalol for suppression of recurrent symptomatic atrial fibrillation. Am J
Cardiol 1993;71:558–563.
5. Juul-Mo
¨ller S, Edvardsson N, Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion
of atrial fibrillation. Circulation 1990;82:1932–1939.
6. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL,
Halperin JL, Kay GN, Klein WW, Levy S, McNamara RL, Prystowsky EN,
20.
21.
22.
23.
24.
25.
Downloaded from by guest on October 21, 2014
In patients with symptomatic persistent first-time cardioverted AF, we advocate a strategy of pre-treatment with
metoprolol CR in combination with prompt cardioversion in
case of early relapse (1–6 weeks). This strategy significantly
increases the number of patients in SR during 6 months of
follow-up. The treatment is both safe and well tolerated,
and our strategy offers an advantageous alternative to traditional antiarrhythmic treatment.
Wann LS, Wyse DG;. American College of Cardiology; American
Heart Association; European Society of Cardiology; North American
Society of Pacing and Electrophysiology. ACC/AHA/ESC guidelines for
the management of patients with atrial fibrillation. Eur Heart J 2001;
22:1852–1923.
Plewan A, Lehmann G, Ndrepepa G, Schreieck J, Alt EU, Schomig A,
Schmitt C. Maintenance of sinus rhythm after electrical cardioversion
of persistent atrial fibrillation; sotalol vs. bisoprolol. Eur Heart J 2001;
22:1504–1510.
Ku
¨hlkamp V, Schirdewan A, Stangl K, Homberg M, Ploch M, Beck O. Use of
Metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled
study. J Am Coll Cardiol 2000;36:139–146.
¨ stergren J, Rosenqvist M. Factors
Frick M, Frykman V, Jensen-Urstad M, O
predicting sucess rate and recurrence of atrial fibrillation after first electrical cardioversion in patients with persistent atrial fibrillation. Clin
Cardiol 2001;24:238–244.
Tieleman RG, Van Gelder IC, Crijns HJ De Kam PJ, Van Den Berg MP,
Haaksma J, Vand Der Woude HJ, Allessie MA. Early recurrences of
atrial fibrillation after electrical cardioversion: a result of
fibrillation-induced electrical remodelling of the atria? J Am Coll
Cardiol 1998;31:167–173.
Wijffels M, Kirchhof C, Dorland R, Allessie M. Atrial fibrillation begets
atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995;92:1954–1968.
Goette A, Honeycutt C, Langerg JJ. Electrical remodelling in atrial
fibrillation. Time course and mechanisms. Circulation 1996;94:
2968–2974.
Lombardi F, Colombo A, Basilico B, Ravaglia R, Garbin M, Vergani D,
Battezzati PM, Fiorentini C. Heart rate variability and early recurrence
of atrial fibrillation after electrical cardioversion. J Am Coll Cardiol
2001;37:157–162.
Schotten U, Duytschaever M, Ausma J, Eijsbouts S, Neuberger HR,
Allessie M. Electrical and contractile remodelling during the first day of
atrial fibrillation go hand in hand. Circulation 2003;107:1433–1439.
Bertaglia E, D‘Este D, Zerbo F, Zoppo F, Delise P, Pascotto P. Success of
serial external electrical cardioversion of persistent atrial fibrillation in
maintaining sinus rhythm; a randomized study. Eur Heart J 2002;23:
1522–1528.
Coumel P. Neural aspects of paroxysmal atrial fibrillation. In: Falk RH,
Podrid PJ, (ed.), Atrial Fibrillation Mechanisms and management.
New York, Raven Press; 1992. 109–125.
Campbell DL, Rasmusson RL, Comer MB, Strauss HC. The cardiac
calcium-independent outward potassium current; kinetics, molecular
properties, and role in ventricular repolarization. In: Zipes DP, Jalife J,
(ed.), Cardiac Electrophysiology; From cell to bedside. 2nd ed. Philadelphia, Saunders; 1995. 83–96.
Daoud EG, Bogun F, Goyal R, Harvey M, Man KC, Strickberger SA,
Morady F. Effect of atrial fibrillation on atrial refractoriness in humans.
Circulation 1996;94:1600–1606.
Steeds RP, Birchall AS, Smith M, Channer KS. An open label, randomised,
crossover study comparing sotalol and atenolol in the treatment of symptomatic paroxysmal atrial fibrillation. Heart 1999;82:170–175.
Yu WC, Lee SH, Tai CT, Tsai CF, Hsieh MH, Chen CC, Ding YA, Chang MS,
Chen SA. Reversal of atrial electrical remodelling following cardioversion
of long-standing atrial fibrillation in man. Cardiovasc Res 1999;42:
470–476.
Tanabe Y, Chinushi M, Taneda K, Fujita S, Kasai H, Yamaura M, Imai S,
Aizawa Y. Recovery of the right effective refractory period after cardioversion of chronic atrial fibrillation. Am J Cardiol 1999;84:1261–1264.
Fynn S, Todd D, Hobbs J, Armstrong K, Firzpatrick A, Garratt C. Clinical
evaluation of a policy of early repeated internal cardioversion for
recurrence of atrial fibrillation. J Cardiovasc Elctrophysiol 2002;13:
135–141.
Daoud EG, Hummel JD, Augostini R, Williams S, Kalbfleisch SJ. Effect of
verapamil on immediate recurrence of atrial fibrillation. J Cardiovasc
Electrophysiol 2000;11:1231–1237.
Villani GO, Piepoli MF, Terracciano C, Capucci A. Effects of diltiazem pretreatment on direct-current cardioversion in patients with persistent
atrial fibrillation; A single-blind, randomized, controlled study. Am
Heart J 2000;140:437–443.
Van Noord T, Tieleman RG, Bosker HA, Kingma T, van Veldhuisen DJ,
Crinjns H, van Gelder IC. Beta-blockers prevent subacute recurrences
of persistent atrial fibrillation only in patients with hypertension. Europace 2004;6:343–350.
Effects of metoprolol on maintenance of SR
26. Brundel BJ, van Gelder IC, Henning RH, Tuinenburg AE, Deelman LE,
Tieleman RG, Grandjean JG, van Gilst WH, Crijns HJ. Gene expression
of proteins influencing the calcium homeostasis in patients with persistent and paroxysmal atrial fibrillation. Cardiovasc Res 1999;42:443–454.
27. Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and
safety of quinidine therapy for maintenance of sinus rhythm after
1357
cardioversion. A meta-analysis of randomized control trials. Circulation
1990;82:1106–1116.
28. Flaker GC, Blackshear JL, McBride R, Kronmal RA, Halperin JL, Hart RG.
Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation.
The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll
Cardiol 1992;20:572–532.
Clinical vignette
doi:10.1093/eurheartj/ehl451
Online publish-ahead-of-print 2 January 2006
Bhavna Mohandas, Balkrishna Singh, Jawahar L. Mehta, and Rajesh Sachdeva *
University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, 4301 W. Markham Street,
532 Little Rock, AR 72205, USA;
*Corresponding author. Tel: þ1 501 603 1268; fax: þ1 501 686 8319. E-mail address: rsachdeva@uams.edu
A 52-year-old Caucasian male presented with shortness of breath
and exertional fatigue. A persatine cardiolyte stress test showed a
large inferolateral wall reversible defect. Coronary angiography
showed four coronary arteries, each arising from a separate
ostium. The right coronary artery (RCA) and left circumflex (LCx)
artery originated from the two separate ostia in the right coronary
sinus (Panels A, C, and D). The left anterior descending (LAD) and
ramus intermedius (RI) arteries originated from two separate ostia
in the left coronary sinus (Panels B and D). The RCA had proximal
chronic total occlusion, and the LCx artery had 60% intermediate
stenosis in the proximal segment. The LCx had a posterior course
(Panel D). There was 80% focal stenosis of the first diagonal branch
of LAD and 70% focal stenosis of the RI in the proximal segment.
There are two hypotheses regarding development of epicardial
arteries. First, there are two endothelial buds arising from the
truncus arteriosus, which give rise to two coronary arteries.
Secondly, there are six endothelial buds arising from each sinus
of the truncus arteriosus, of which four involutes and coronary
arteries arise from the remaining two. The presence of four coronary arteries from two coronary sinuses can be explained by the
abnormal septation of two endothelial buds or the involution of
two from six endothelial buds.
Not much is known about the risk entailed when early atherosclerosis is found in such abnormal coronary arteries. With the
advent of imaging modalities such as CT angiogram, accurate diagnosis especially of the origin and course of the coronary arteries is
possible. This is important in diagnosing potentially high-risk
anomalies and involvement of atherosclerotic process.
Panel A. Left anterior oblique projection showing separate origin of RCA and LCx arteries from the right coronary sinus. RCA is totally
occluded in the proximal segment.
Panel B. Antero-posterior caudal projection showing separate origin of LAD artery and RI artery from the left coronary cusp.
Panel C. Left anterior oblique projection showing separate origin of RCA and LCx artery from the right coronary sinus. RCA has a stent.
Panel D. Multiplanar reconstruction of coronary CT angiogram (global view) demonstrating four separate coronary ostia. Anomalous
origin of LCx and RCA from the right coronary sinus and their course are evident. RCA has a stent. Separate origin of the LAD and RI arteries
from the left coronary sinus is also noticeable.
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A man with four coronary arteries