Comparison of Response to Cardiac
Resynchronization Therapy in Patients
With Sinus Rhythm Versus Chronic
Atrial Fibrillation
Sander G. Molhoek, MD, Jeroen J. Bax, MD, Gabe B. Bleeker, MD, Eric Boersma,
L. van Erven, MD, Paul Steendijk, PhD, Ernst E. van der Wall, MD, and
Martin J. Schalij, MD
Cardiac resynchronization therapy (CRT) is a new ther-
apeutic option for patients who have drug-refractory
end-stage heart failure. Much information has been ob-
tained from patients who have sinus rhythm, but the use
of CRT in patients who have chronic atrial fibrillation (AF)
has not been studied extensively. Accordingly, we eval-
uated the clinical response and long-term survival rate
of CRT in patients who had heart failure and chronic AF,
and the results were compared with those in patients
who had sinus rhythm and who underwent CRT. Sixty
patients who had end-stage heart failure (30 had sinus
rhythm and 30 had chronic AF), New York Heart Asso-
ciation classes III to IV, left ventricular ejection fraction
<35%, QRS interval >120 ms, and a left bundle branch
block received a biventricular pacemaker. New York
M any patients who have severe congestive heart
failure also develop chronic atrial fibrillation
(AF), and cardiac resynchronization therapy (CRT)
has been shown to improve symptoms, exercise ca-
pacity, and systolic left ventricular function in these
patients.1 8 Two issues remain unresolved in patients
who have AF. First, different studies have shown that
20% to 30% of patients who have sinus rhythm do not
respond to CRT, despite adequate selection criteria4; it
is unknown whether the number of nonresponders to
CRT is comparable to patients who have AF. Second,
the long-term benefit of CRT in patients who have AF
has not been demonstrated. These issues are addressed
in the present study.
METHODS
Patients and study design: Based on traditional se-
lection criteria of patients who have drug-refractory
heart failure (New York Heart Association [NYHA]
From the Department of Cardiology, Leiden University Medical Center,
Leiden; and the Department of Epidemiology and Statistics, Erasmus
University Rotterdam, Rotterdam, The Netherlands. Dr. Molhoek re-
ceived grant 2001D015, and Dr. Bleeker received grant 2002B109
from the Dutch Heart Foundation, The Hague, and the Interuniversity
Cardiology Institute of Netherlands, Utrecht, The Netherlands. Manu-
script received June 14, 2004; revised manuscript received and
accepted August 11, 2004.
Address for reprints: Jeroen J. Bax, MD, Department of Cardiol-
ogy, Leiden University Medical Center, Albinusdreef 2, 2333 ZA
Leiden, The Netherlands. E-mail: jbax@knoware.nl.
1506 2004 by Excerpta Medica Inc. All rights reserved.
The American Journal of Cardiology Vol. 94 December 15, 2004
PhD,
Heart Association class, Minnesota Quality of Life score,
and 6-minute walking distance were evaluated at base-
line and after 6 months of CRT. Long-term follow-up was
<2 years. New York Heart Association class, Minnesota
Quality of Life score, and 6-minute walking distance
improved significantly in the 2 groups after 6 months of
CRT. The number of nonresponders was greater among
patients who had AF. Nevertheless, the long-term sur-
vival rate was comparable between patients who had
sinus rhythm and those who had AF. Patients who had
AF demonstrated comparable benefit from CRT as those
who had sinus rhythm. 2004 by Excerpta Medica
Inc.
(Am J Cardiol 2004;94:1506 1509)
class III or IV, left ventricular ejection fraction 35%,
QRS duration 120 ms or 200 ms for a paced QRS,
and left bundle branch block configuration), 30 con-
secutive patients who had sinus rhythm and 30 con-
secutive patients who had AF underwent implantation
of a CRT device. All patients who had AF had a
persistent type (3 months). All subjects are part of a
prospective registry on the clinical evaluation of pa-
tients who receive a CRT device.
Pacemaker implantation: Despite the presence of
persistent AF, all patients received a 3-lead pacing
system. A left ventricular pacing lead (Easytrack
4512-80, Guidant, St. Paul, Minnesota; Attain-SD
4189, Medtronic Inc., St. Paul, Minnesota) was in-
serted transvenously along the subclavian route. A
coronary sinus venogram was obtained during balloon
occlusion, and the left ventricular pacing lead was
inserted through the coronary sinus with help of a
dedicated 8Fr guiding catheter. The lead was ad-
vanced as far as possible into the venous system,
preferably in the posterolateral region. The other leads
were positioned in the high right atrium and in the
right ventricle. Leads were connected to a dual-cham-
ber biventricular pacemaker (26 Contak TR, Guidant;
6 InSync III, Medtronic Inc.). In 28 patients (15 had
sinus rhythm and 13 had AF), a conventional indica-
tion existed for a defibrillator, and these patients re-
ceived a combined device (26 Contak Renewal CD,
Guidant; 2 InSync CD, Medtronic Inc.). If sinus
rhythm was present, the pacemaker was programmed
0002-9149/04/$see front matter
doi:10.1016/j.amjcard.2004.08.028
 TABLE 1 Characteristics of Patients Who Had Sinus Rhythm (n 30) and Atrial Fibrillation (n 30) at Baseline and Six-Month
Follow-up
Sinus Rhythm AF
(n 30) (n 30)

Parameters Baseline 6 Months p Value Baseline 6 Months p Value

Men/Women 24/6 27/3

Age (yrs) 68 8 63 10
NYHA class 3.2 0.4 2.2 0.8 0.05 3.2 0.4 2.3 0.6 0.05
Quality of life score 43 13 28 15 0.05 43 17 32 21 0.05
6-Minute walking test (m) 262 97 388 141* 0.05 227 113 326 155* 0.05
LV ejection fraction (%) 23 8 32 12 0.05 20 11 27 8 0.05
LV end-diastolic diameter (cm) 7.4 2.8 6.7 2.1 0.05 7.6 3.1 6.5 1.8 0.05
LV end-systolic diameter (cm) 6.8 2.7 6.1 2.2 0.05 6.7 1.9 6.3 2.2 0.05

*p 0.05, sinus rhythm versus AF after 6 months of CRT.

LV left ventricular.

in the DDDR mode; in patients who had AF, the
pacemaker was switched to the VVI-R mode.
Clinical evaluation: At baseline and after 6 months
of CRT, patients were clinically evaluated. Heart fail-
ure symptoms were classified with the NYHA score.
Quality of life score was assessed with the Minnesota
Living With Heart Failure questionnaire.9 This ques-
tionnaire contains 21 questions concerning the pa-
tients perception of the effects of heart failure on
daily-life activities. Questions are scored from 0 to 5,
resulting in a total score from 0 to 105, with the
highest score reflecting the worst quality of life. QRS
duration and morphology were measured from the
surface electrocardiogram by 2 independent observ-
ers. Exercise capacity was evaluated by assessing a
6-minute walking distance.10 Two-dimensional echo-
cardiography at rest was performed at baseline and
6-month follow-up to assess left ventricular ejection
fraction. From the apical 2- and 4-chamber images,
left ventricular ejection fraction was determined by
using the biplane Simpsons rule.11 Interrogation of
the device showed the percentage of ventricular pac-
ing in patients who had AF over 6 months of CRT.
Long-term follow-up: Long-term follow-up was per-
formed by chart review, telephone contact, and out-
patient clinical visits. Follow-up data were acquired
for 2 years. Events were classified as cardiac death
(defined by a hospital chart that documented arrhyth-
mic death, sudden cardiac death, or death attributable
to congestive heart failure or myocardial infarction),
nonfatal myocardial infarction, and congestive heart
failure that required hospitalization. Moreover, the
average length of hospital stay per patient (expressed
as days per year) was compared before and after
pacemaker implantation.
Statistical analysis: Data are expressed as mean
SD. Comparison of data were performed with Stu-
dents t test for paired and unpaired data when appro-
priate. In case of non-normal distribution of data, the
Mann-Whitney U statistic test was used. Univariate
analysis for categorical variables was performed by
using chi-square test with Yates correction. Simulta-
neous comparison of 2 mean values was performed
by 1-way analysis of variance with Bonferronis cor-
rection. For all tests, a p value 0.05 was considered
statistically significant.
RESULTS
Baseline characteristics: Thirty consecutive patients
who had sinus rhythm and 30 consecutive patients
who had AF underwent CRT and were included in the
study. The study population comprised 51 men and 9
women (mean age 65 9 years). Underlying etiology
was nonischemic in 31 patients (52%) and ischemic in
29 patients (48%). Mean NYHA class was 3.2 0.4,
with most patients (80%) in NYHA class III. Medi-
cation included diuretics in all patients, angiotensin-
converting enzyme inhibitors in 90%, blockers in
50%, spironolactone in 39%, and amiodarone in 27%;
all patients also used anticoagulants. Of the 30 pa-
tients who had AF, 17 (57%) required permanent
ventricular pacing due to previous atrioventricular
junction ablation (18 6 months before CRT). There
were no significant differences in baseline character-
istics between patients who had sinus rhythm and
those who had AF (Table 1).
Six-month follow-up: clinical evaluation: In patients
who had sinus rhythm (n 30), mean QRS duration
on the electrocardiogram decreased from 180 33 ms
to 160 21 ms (p 0.05). Mean NYHA class de-
creased from 3.2 0.4 to 2.2 0.8 (p 0.05) after 6
months of CRT. The 6-minute walking distance im-
proved significantly by 76%, and the quality of life
score decreased by 28%. Of note, 21 patients (70%)
had a 25% improvement in walking distance at
6-month follow-up and 17 patients (57%) had a de-
crease of 25% in quality of life score. Left ventric-
ular ejection fraction increased significantly after 6
months of CRT (Table 1).
In patients who had AF, mean QRS duration de-
creased from 205 15 ms to 164 35 ms (p 0.05).
Mean NYHA class decreased from 3.2 0.4 to 2.3
0.6 (p 0.05) after 6 months of CRT. In addition, the
6-minute walking distance increased significantly by
66% (p 0.05), and the quality of life score decreased
by 19% (p 0.05). Of note, 18 patients (60%) showed
an improvement of 25% in walking distance at
6-month follow-up and 14 patients (47%) had a de-

HEART FAILURE/RESPONSE TO CRT IN PATIENTS WITH SINUS RHYTHM AND AF 1507

 TABLE 2 Characteristics of Patients Who Had Atrial Fibrillation (n 30) With and Without Atrioventricular Node Ablation at
Baseline and Six-Month Follow-up
Node Ablation
(n 17)
Parameters Baseline 6 Months
NYHA class 3.1 0.3 2.2 0.5
Quality of life score 42 19 28 21
6-Minute walking test (m) 229 125 388 172
LV ejection fraction (%) 21 7 30 12
Abbreviation as in Table 1.
crease 25% in quality of life score. Left ventricular
ejection fraction increased from 20 11% to 27
8% (p 0.05) after 6 months of CRT (Table 1). When
patients who had AF and atrioventricular node abla-
tion were compared with those who had AF and no
ablation, clinical improvement was comparable be-
tween groups (Table 2). However, in patients who did
not have atrioventricular node ablation, percent ven-
tricular pacing was 82% versus 100% in patients who
had ablation (p 0.05).
Responders were defined as those patients who
improved 1 class in NYHA score after 6 months of
CRT. At 6-month follow-up, 43 patients (72%) were
accordingly classified as responders and 17 (28%) as
nonresponders. There was a significant difference be-
tween the percentage of responders in the sinus
rhythm group (n 24, 80%) compared with the AF
group (n 19, 64%; p 0.05). In the AF group, there
was a difference in percentage of clinical responders
that favored patients who had atrioventricular node
ablation compared with patients who did not have
ablation (71% vs 54%, p NS).
Follow-up data: Patients who had sinus rhythm
were hospitalized for congestive heart failure an av-
erage of 3.9 4.8 days/year before pacemaker im-
plantation compared with 0.5 1.5 days/year after
implantation (p 0.05). The number of annual hospi-
talizations per patient decreased from 0.8 0.9 before
implantation to 0.2 0.4 after implantation
(p 0.05). Mean follow-up of patients who had sinus
rhythm was 25 9 months (range 8 to 37). During
follow-up, 3 patients (10%) died due to end-stage
heart failure (Figure 1). After 2 years of follow-up,
mean NYHA class remained significantly decreased,
from 3.2 0.4 to 2.3 1.0 (p 0.05), and quality of
life score remained decreased, from 43 13 to 30
19 (p 0.05). Patients who had AF were hospitalized
for congestive heart failure on average 4.1 4.8
days/year before CRT versus 0.7 1.8 days/year after
implantation (p 0.05). The number of annual hospi-
talizations per patient decreased from 0.9 1.0 before
implantation to 0.3 0.5 after implantation
(p 0.05). Mean follow-up of patients who had AF
was 19 11 months (range 4 to 46). During follow-
up, 7 patients (23%) died, 6 (20%) due to end-stage
heart failure and 1 to a noncardiac cause. After 2 years
of follow-up, mean NYHA class remained decreased,
from 3.2 0.4 to 2.4 0.8 (p 0.05), and the quality
of life score also remained decreased, from 43 17 to
1508 THE AMERICAN JOURNAL OF CARDIOLOGY VOL. 94
No Node Ablation
(n 13)
p Value Baseline 6 Months p Value
0.05 3.2 0.4 2.4 0.7 0.05
0.05 44 13 37 22 NS
0.05 224 101 310 134 0.05
0.05 19 9 26 10 0.05
33 24 (p 0.05). When survival rate was compared
between patients who had sinus rhythm and those who
had AF, mortality rate was not statistically different
between groups, although patients who had AF tended
to have a higher mortality rate (10% vs 23%, p
0.07). The actual survival curves of the 2 groups are
shown in Figure 1.
DISCUSSION
In the present study, the benefit of CRT in patients
who had AF was compared with that in patients who
had sinus rhythm. The main findings are that (1)
benefit, as measured by clinical parameters (NYHA
class, exercise capacity, and quality of life score), was
comparable between patients who had sinus rhythm
and those who had AF; (2) the number of nonre-
sponders was higher among patients who had AF; (3)
the decrease in hospitalization rate was comparable
between patients who had AF and those who had sinus
rhythm; and (4) long-term survival rate on CRT was
comparable between patients who had sinus rhythm
and those who had AF. Different studies have dem-
onstrated the benefit of CRT in patients who have
heart failure.4 6 These studies showed improvements
in symptoms, exercise capacity, and systolic left ven-
tricular function.4 6 In addition, a decrease in hospi-
talization for decompensated heart failure was found,
as was a favorable mid-term survival rate with CRT
versus optimal medical therapy.4 6
Recent studies have focused on the benefit of CRT
in patients who have AF and demonstrated that pa-
tients who have AF may benefit from this thera-
py.5,12,13 Etienne et al 12 reported an acute improve-
ment in hemodynamics immediately after CRT in 11
patients who had AF. In a substudy from the Multisite
Stimulation in Cardiomyopathies trial,13 37 patients
who had AF showed improved clinical parameters
after a 3-month period of active CRT. In particular, a
10% improvement in 6-minute walking distance and a
13% improvement in peak oxygen consumption were
shown. Mortality rate at 9-month follow-up was 11%.
In the present study, similar results were obtained.
Patients who had sinus rhythm and those who had AF
exhibited benefit from CRT, and these patients dem-
onstrated significant improvement in clinical parame-
ters. The response to CRT in patients who have AF is
currently unclear. Careful analysis of data from the
Multicenter InSync Randomized Clinical Evaluation
(MIRACLE) trial has shown that 20% to 30% of
DECEMBER 15, 2004

FIGURE 1. Mortality curves of patients who had heart failure
with sinus rhythm (n 30) and AF (n 30).
patients did not respond to CRT.4 In the present study,
we found that the number of responders was greater
among patients who had sinus rhythm than among
those who had AF. Of interest, when patients who had
AF were separated into those who had previous atrio-
ventricular node ablation and those who did not, the
benefit seemed to be greater in patients who had
previous ablation. Leon et al14 evaluated 20 patients
who had AF, heart failure, and permanent right ven-
tricular pacing after atrioventricular node ablation
whose treatment had been upgraded to CRT. These
patients exhibited a 33% improvement in quality of
life score and a 44% improvement in left ventricular
ejection fraction, values that were higher than the
modest improvements observed in previous studies of
patients who had AF and who underwent CRT.12,13 In
these previous studies, substantial percentages of pa-
tients who had AF did not undergo atrioventricular
node ablation. A partial explanation for the greater
benefit in patients who had ablation may be that atrio-
ventricular node ablation ensures 100% ventricular
stimulation, whereas only 82% ventricular pacing was
obtained during CRT even with optimized rate control
in our patients who did not have ablation. These
observations suggest that atrioventricular node abla-
tion may be beneficial to achieve maximal benefit
from CRT in patients who have AF. In addition to the
improvement in clinical parameters, hospitalization
for decompensated heart failure was significantly de-
creased after CRT in patients who had sinus rhythm
and those who had AF. This observation is in line with
previous studies that reported an 80% decrease in
hospitalization rates in patients who had sinus
rhythm.4 6
The long-term survival rate of patients who have
AF and who undergo CRT has not been evaluated
HEART FAILURE/RESPONSE TO CRT IN PATIENTS WITH SINUS RHYTHM AND AF
previously, and the results in the present study indi-
cate a comparable survival rate between patients who
have sinus rhythm and those who have AF. However,
the number of patients evaluated is small, and larger
studies are needed to further evaluate long-term sur-
vival rates after CRT in patients who have AF. A
limitation of the present study is that patients who had
sinus rhythm were programmed to have a lower rate of
50 beats/min and those who had AF were programmed
to have a lower rate of 70 beats/min, and these pro-
grammed heart rates may have affected the observed
outcomes. Another limitation is the inclusion of pa-
tients who previous atrioventricular node ablation and
those who did not. Patients who had previous atrio-
ventricular node ablation received right ventricular
pacing at the time of implantation of the CRT device,
which may have altered left ventricular synchrony.
This may have influenced the current results, and
further studies are needed in patients who have atrio-
ventricular node ablation and those who do not.
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