Download Adverse Effect of Ventricular Pacing on Heart Failure and

Adverse Effect of Ventricular Pacing on Heart Failure and
Atrial Fibrillation Among Patients With Normal Baseline
QRS Duration in a Clinical Trial of Pacemaker Therapy for
Sinus Node Dysfunction
Michael O. Sweeney, MD; Anne S. Hellkamp, MS; Kenneth A. Ellenbogen, MD;
Arnold J. Greenspon, MD; Roger A. Freedman, MD; Kerry L. Lee, PhD; Gervasio A. Lamas, MD;
for the MOde Selection Trial (MOST) Investigators
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Background—Dual-chamber (DDDR) pacing preserves AV synchrony and may reduce heart failure (HF) and atrial
fibrillation (AF) compared with ventricular (VVIR) pacing in sinus node dysfunction (SND). However, DDDR pacing
often results in prolonged QRS durations (QRSd) as the result of right ventricular stimulation, and ventricular
desynchronization may result. The effect of pacing-induced ventricular desynchronization in patients with normal
baseline QRSd is unknown.
Methods and Results—Baseline QRSd was obtained from 12-lead ECGs before pacemaker implantation in MOST, a
2010-patient, 6-year, randomized trial of DDDR versus VVIR pacing in SND. Cumulative percent ventricular paced
(Cum%VP) was determined from stored pacemaker data. Baseline QRSd ⬍120 ms was observed in 1339 patients (707
DDDR, 632 VVIR). Cum%VP was greater in DDDR versus VVIR (90% versus 58%, P⫽0.001). Cox models
demonstrated that the time-dependent covariate Cum%VP was a strong predictor of HF hospitalization in DDDR
(hazard ratio [HR], 2.99 [95% CI, 1.15 to 7.75] for Cum%VP ⬎40%) and VVIR (HR 2.56 [95% CI, 1.48 to 4.43] for
Cum%VP ⬎80%). The risk of AF increased linearly with Cum%VP from 0% to 85% in both groups (DDDR, HR 1.36
[95% CI, 1.09, 1.69]; VVIR, HR 1.21 [95% CI 1.02, 1.43], for each 25% increase in Cum%VP). Model results were
unaffected by adjustment for known baseline predictors of HF hospitalization and AF.
Conclusions—Ventricular desynchronization imposed by ventricular pacing even when AV synchrony is preserved
increases the risk of HF hospitalization and AF in SND with normal baseline QRSd. (Circulation. 2003;107:29322937.)
Key Words: pacing 䡲 heart failure 䡲 fibrillation
T
he optimal pacing mode for symptomatic bradycardia
caused by sinus node dysfunction (SND) is still debated.
Though maintenance of atrioventricular (AV) synchrony
afforded by dual-chamber pacing is intuitively superior to
ventricular pacing, this has been surprisingly difficult to
prove. Large randomized clinical trials have reached consensus that there is no survival benefit in patients that are
dual-chamber paced. However, the same trials have produced
inconsistent results regarding the effect of pacing mode on
cardiovascular morbidity.1–3 One possible explanation is that
ventricular desynchronization imposed by right ventricular
apical pacing in the dual-chamber mode has adverse longterm effects that mitigate the benefit of AV synchrony.
This study tested the hypothesis that ventricular desynchronization imposed by right ventricular apical pacing even
when AV synchrony is preserved increases the risk of heart
failure hospitalization (HFH) and atrial fibrillation (AF) in
patients with SND and normal baseline QRS duration.
Methods
The study population was extracted from the MOde Selection Trial
(MOST), a 6-year, prospective, randomized comparison of singlechamber ventricular rate modulated (VVIR) pacing versus dualchamber rate modulated (DDDR) pacing in 2010 patients with
SND.1
Eligible patents received DDDR pacing systems for SND and
were in sinus rhythm at the time of their random assignment.
Received December 23, 2002; revision received March 17, 2003; accepted March 17, 2003.
From Brigham and Women’s Hospital and Harvard Medical School (M.O.S.), Boston, Mass; Duke Clinical Research Institute and Duke University
Medical School (A.S.H., K.L.L.), Durham, NC; Medical College of Virginia (K.A.E.), Richmond, Va; Jefferson Medical College (A.J.G.), Philadelphia,
Pa; University of Utah Health Sciences Center (R.A.F.), Salt Lake City; and Mt Sinai Medical Center (G.A.L.), Miami, Fla.
Dr Sweeney is a paid consultant to Medtronic, Inc. Dr Freedman is a paid consultant to Guidant Corporation.
Correspondence to Michael O. Sweeney, MD, Cardiac Arrhythmia Service, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail
[email protected]
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000072769.17295.B1
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Sweeney et al
Effect of Ventricular Pacing on Heart Failure and AF
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Ventricular pacing leads were placed at the right ventricular apex.
For both groups, the lower rate was programmed to ⱖ60 and the
upper rate ⱖ110 beats per minute. For the DDDR group, the
programmed AV delay was recommended to be in the optimal
physiological range (120 to 200 ms).4
Before pacemaker implantation, baseline demographic and clinical data were collected and QRS duration was determined from
12-lead ECGs. Normal QRS duration was defined as ⬍120 ms.
Abnormal AV conduction (including first-degree AV block) was
present in 16% of DDDR and 20% of VVIR patients.
Median follow-up was 33.1 months. The MOST secondary end
points of HFH and AF were used in this study.1 A Clinical Events
Committee blinded to assigned pacing mode adjudicated all first
HFHs. Subsequent HFHs were defined by a primary diagnosisrelated grouping (DRG) code of congestive heart failure. An ECG
Core Laboratory, blinded to pacing mode, confirmed incident cases
of AF.
Percent ventricular paced was determined from stored pacemaker
diagnostic data at each follow-up visit. For each patient, cumulative
percent ventricular paced (Cum%VP) from random assignment to
each day of follow-up was calculated by (1) finding, for each visit,
the mean percent ventricular paced over all visits up to and including
that visit, weighted by the number of days between visits, and (2)
using linear interpolation to determine the values for days between
visits. Cumulative percent atrial paced (Cum%AP) was calculated
similarly.
For summarizing event rates, Cum%VP categories were created
by using the value at the time of the event for patients with events
and the value at the end of follow-up for patients without events.
Statistical Analysis
Cum%VP was compared between pacing modes by means of a
Wilcoxon rank-sum test.
The relation of Cum%VP to first HFH and first incidence of AF
was assessed by means of Cox proportional hazards models,5 with
time to event as the dependent variable and Cum%VP as a timedependent covariate. HFH models were extended to include multiple
HFHs by use of Cox models that allow multiple events per patient.6
Both unadjusted models (Cum%VP as the only predictor) and
adjusted models (adjusted for other known baseline predictors,
determined from multivariable analysis on all MOST patients) were
generated. HFH models were adjusted for prior heart failure, ejection
fraction, antiarrhythmic therapy, and Karnofsky score.7 Other potential adjustment variables— cardiac medications (aspirin, ACE inhibitors, diuretics, ␤-blockers, calcium channel blockers), baseline
rhythm, left ventricular hypertrophy, hypertension, and lower pacing
rate—were found to be unrelated to HFH and were not included in
any model. AF models were adjusted for prior AF, antiarrhythmic
therapy, congestive heart failure, mitral regurgitation, and AV block.
Cum%AP was used in adjusted AF models in DDDR patients.
Initial examination of the data showed, within each pacing mode,
that the relation between Cum%VP and both end points could be
characterized by using 2-part linear spline functions, for example, the
relations were allowed to have different slopes over different parts of
the range of percent pacing. For each end point and each pacing
mode, the point at which the slope of the risk relation changed was
chosen to give the best model fit. With the use of the Cox model,
tests of whether the slope parameters were different from zero on
either side of the change point were performed to assess whether risk
was level over some part of the range and whether a more
parsimonious model could be used with values truncated above or
below a certain point. Because data were sparse over some parts of
the range, and as an alternative way of describing the results, models
were used for the HFH end point that categorized Cum%VP as being
above or below the change point. Relative risk is expressed as a
hazard ratio (95% confidence interval) (HR [CI]). In all models,
patients who were permanently changed to the other pacing mode
were censored at the time of crossover.
Because of the difficulty in displaying time-dependent covariates
graphically, percent ventricular paced during the first 30 days, which
correlated well with Cum%VP over all of follow-up (r⫽0.76), was
TABLE 1.
2933
Baseline Characteristics of the Study Population
Baseline Characteristic*
Age, y
DDDR
(n⫽707)
73 (66, 79)
VVIR
(n⫽632)
74 (67, 80)
Female
50% (356)
51% (324)
Prior myocardial infarction
26% (185)
21% (133)
Ejection fraction, %
57 (50, 62)
55 (50, 63)
Prior CHF
18% (125)
16% (100)
NYHA CHF class I or II
83% (580)
87% (541)
PCI
13% (93)
13% (79)
CABG
19% (131)
18% (115)
56% (399)
52% (329)
Atrial fibrillation
47% (331)
40% (254)
Other atrial tachycardia
20% (142)
21% (131)
180 (160, 200)
190 (160, 220)
Cardiac procedures
Prior atrial tachycardia
PR interval, ms
CHF indicates congestive heart failure; NYHA, New York Heart Association
functional class; PCI, percutaneous coronary intervention; CABG, coronary
artery bypass surgery; and AV, atrioventricular.
*Categorical variables are percent (No.); continuous variables are median
(25th, 75th percentiles).
used to define percent pacing groups for Kaplan-Meier plots.8 For
HFH plots, groups were defined by the points of change in the risk
relations for the models (above). For the AF plots, because there
were no points of change in the slope of the risk relation within the
range of interest, groups of ⱕ40%, 40% to 70%, and 70% to 90%
paced were chosen as dividing the range roughly into thirds.
Results
Baseline QRS Duration and Cum%VP
Baseline QRS duration and Cum%VP data were available in
1732 of 2010 (86.2%) patients. Baseline QRS duration ⬍120
ms was observed in 1339 of 1732 (77.3%). Of these 1339,
707 (52.8%) were randomly assigned to DDDR and 632
(47.2%) to VVIR.
Most patients had normal left ventricular function (median
ejection fraction, 55%) and mild or no symptoms of congestive heart failure (Table 1). More than half had a history of
atrial tachycardia. The baseline PR interval was normal
(⬍200 ms) or mildly prolonged in most patients.
Cum%VP was significantly higher in the DDDR versus the
VVIR group (median [25th, 75th percentile], 90% [57, 99]
versus 58% [20, 86]; P⫽0.001). Fifty percent of the DDDR
group were ventricular paced continuously or near continuously (⬎90% of the time) compared with only 20% in the
VVIR group. Reciprocally, a smaller percentage of the
DDDR group (7%) was infrequently ventricular paced
(⬍10% of the time) compared with the VVIR group (15%).
The higher incidence of Cum%VP in the DDDR group is due
to the overlap of baseline PR intervals with programmed AV
delays in most patients.
Heart Failure Hospitalization
Of 1339 patients in this analysis, 128 (9.6%) had at least one
adjudicated HFH. The DDDR and VVIR paced groups
demonstrated a somewhat different pattern of increase in rate
2934
Circulation
June 17, 2003
TABLE 2. Rates of Heart Failure Hospitalization and Atrial Fibrillation by Pacing
Mode and Cumulative Percent Ventricular Paced
DDDR (n⫽707)
Cum%VP
⬍10%
N
HFH,
n (%)
N
VVIR (n⫽632)
AF,
n (%)
N
HFH,
n (%)
N
AF,
n (%)
48
1 (2)
49
8 (16)
97
7 (7)
103
22 (21)
ⱖ10%–50%
110
10 (9)
112
21 (19)
200
12 (6)
191
44 (23)
⬎50%–90%
188
16 (9)
193
61 (32)
203
17 (8)
215
63 (29)
⬎90%
361
44 (12)
347
60 (17)
132
21 (16)
123
22 (18)
Total
707
71 (10)
701
150 (21)
632
57 (9)
632
151 (24)
Cum%VP indicates cumulative percent ventricular paced; HFH, heart failure hospitalization; and AF,
atrial fibrillation.
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of HFH with Cum%VP (Table 2). The overall rate of HFH in
the two pacing modes was similar (10% DDDR, 9% VVIR).
In the DDDR mode, the risk of HFH increased with
increased Cum%VP from 0% pacing up to ⬇40% and was
level for 40% to 100% pacing (test for non-zero slope,
P⫽0.84) (Figure 1a). In a model that truncated values above
40%, the adjusted HR [CI] was 1.54 [1.01 to 2.36]
(P⫽0.046), indicating a 54% relative increase in risk of HFH
for each 10% increase in Cum%VP up to 40%. An adjusted
model that included Cum%VP as a categorical variable
(⬎40% versus ⱕ40%) had an HR [CI] of 2.60 [1.05 to 6.47]
(P⫽0.040), indicating that ventricular pacing ⬎40% of the
time in the DDDR mode was associated with a 2.6-fold
increased risk of HFH compared with pacing ⬍40% of the
time (Table 3).
In the VVIR mode, the shape of the relation between the
risk of HFH and Cum%VP was different versus DDDR
mode. Risk was level between 0% and 80% Cum%VP (test
for non-zero slope P⫽0.28) and increased with increased
Cum%VP from 80% pacing to 100% (Figure 1b). In a model
that truncated values below 80%, the adjusted HR [CI] was
1.96 [1.39, 2.77] (P⫽0.0001), indicating a 96% increased
relative risk for each 10% increase in Cum%VP ⬎80%. An
adjusted model that included Cum%VP as a categorical
variable (⬎80% versus ⱕ80%) had an HR [CI] of 2.50 [1.44
to 4.36] (P⫽0.0012), indicating that ventricular pacing
⬎80% of the time in the VVIR mode was associated with a
2.5-fold increased risk of HFH compared with pacing ⬍80%
of the time (Table 3).
Of the 128 patients who had at least one adjudicated HFH,
38 (29.7%) had ⱖ1 (range, 1 to 6; total, 66) subsequent
HFHs. Thus, 194 HFHs were used to assess the relation of
Cum%VP to HFH, taking all occurrences into account.
Extension of the HFH models to include multiple events
demonstrated that highly paced patients are at greater risk of
HFH (Table 3).
Kaplan-Meier plots relating time to first HFH by Cum%VP
show an early, sustained and increasing incidence of HFH
among DDDR patients with Cum%VP ⬎40% compared with
⬍40% and among VVIR patients with Cum%VP ⬎80%
compared with ⬍80% (Figure 2, a and b).
TABLE 3. Cox Models of the Effect of Cumulative Percent
Ventricular Paced on Heart Failure Hospitalization
Pacing Mode
Hazard Ratio (95% CI)
P
Unadjusted model*
3.01 (1.21, 7.46)
0.018
Adjusted model†
2.60 (1.05, 6.47)
0.040
Cum%VP ⬎40 vs ⱕ40
DDDR
First HFH
All HFH
Unadjusted model*
3.66 (1.44, 9.30)
0.0064
Adjusted model†
2.99 (1.15, 7.75)
0.024
Cum%VP ⬎80 vs ⱕ80
VVIR
First HFH
Unadjusted model*
3.13 (1.86, 5.28)
0.0001
Adjusted model†
2.50 (1.44, 4.36)
0.0012
Unadjusted model*
3.60 (1.93, 6.70)
0.0001
Adjusted model†
2.56 (1.48, 4.43)
0.0007
All HFH
Figure 1. Relation of event risk to cumulative percent ventricular
paced (Cum%VP) as estimated by Cox models with linear spline
functions. Dashed lines represent 95% confidence intervals for
point-by-point estimates of the hazard ratio for a 1% change in
Cum%VP. A, DDDR mode, HFH; b, VVIR mode, HFH; c, DDDR
mode, AF; d, VVIR mode, AF.
Cum%VP indicates cumulative percent ventricular paced; HFH, heart failure
hospitalization.
*Cum%VP as the only predictor.
†Adjusted for other known predictors of HFH.
Sweeney et al
Effect of Ventricular Pacing on Heart Failure and AF
2935
TABLE 4. Cox Models of the Effect of Cumulative Percent
Ventricular Paced on Atrial Fibrillation
Pacing Mode
Hazard Ratio (95% CI)
P
Unadjusted model*
1.018 (1.01, 1.026)
0.0001
Adjusted model†
1.010 (1.002, 1.018)
0.012
Unadjusted model*
1.008 (1.002, 1.015)
0.014
Adjusted model†
1.007 (1.000, 1.014)
0.039
1% Increase in Cum%VP up to 85%
DDDR
1% Increase in Cum%VP up to 80%
VVIR
Cum%VP indicates cumulative percent ventricular paced.
*Cum%VP as the only predictor.
†Adjusted for other known predictors of atrial fibrillation.
Atrial Fibrillation
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The rates of AF increased in both pacing modes as Cum%VP
increased up to ⬇80% to 85%, above which the incidence
tapered off (Table 2). The overall rate of AF was slightly
higher in the VVIR (24%) versus the DDDR (21%) group.
There are 6 fewer DDDR patients in the AF (701) versus the
HFH (707) analysis because 6 patients had AF on the same
day as pacemaker implantation and were excluded from AF
analysis.
Modeling confirmed this pattern, as the risk of AF showed
an increasing relation with increased Cum%VP from 0%
pacing up to ⬇80% or 85% pacing in both pacing modes
(Table 4) (Figure 1, c and d). The risk of AF increased by 1%
for each 1% increase in Cum%VP up to 85% in DDDR. The
risk of AF increased by 0.7% for each 1% increase in
Cum%VP up to 80% in VVIR.
Kaplan-Meier plots relating time to first episode of AF by
Cum%VP show an early, sustained and increasing incidence
of AF among DDDR and VVIR patients with increasing
Cum%VP (Figure 3, a and b).
Discussion
This is the first report of a strong association between
ventricular pacing in the DDDR mode and heart failure in a
clinical trial of pacemaker therapy for symptomatic SND.
Despite maintenance of AV synchrony, ventricular pacing in
the DDDR mode ⬎40% of the time conferred a 2.6-fold
increased risk of HFH compared with less pacing among
similar patients with normal baseline QRS duration. This risk
increased to 3-fold when multiple HFHs were considered.
This provides some evidence that highly paced patients are
not only at greater risk for HFH but are also hospitalized for
heart failure more often. Ventricular pacing in the VVIR
mode ⬎80% of the time was also associated with a significant increased risk of HFH compared with less pacing among
similar patients. This latter observation is consistent with
clinical trials that demonstrated a relative increased incidence
of heart failure in SND treated with ventricular versus atrial
pacing.9 Our observations may explain the previously puzzling dichotomy between the striking benefits of atrial pacing
reported by Andersen et al9 and the more modest benefits of
dual-chamber pacing reported by Connolly et al2 and Lamas
Figure 2. Kaplan-Meier rates for freedom from first HFH by percent ventricular paced during the first 30 days. a, DDDR mode;
b, VVIR mode.
et al.1 This increased risk of HFH associated with increased
Cum%VP in the DDDR and VVIR modes persisted when the
models were adjusted for all other known baseline predictors
of HFH in the study population.
The average risk of HFH in the study population was
⬇10%. The lowest rate of HFH grouped by Cum%VP and
pacing mode was 2% among the DDDR group who were
paced ⬍10% of the time. The shape of the relation between
Cum%VP and risk of HFH was different between DDDR and
VVIR pacing modes. The risk was level above a certain
Cum%VP (40%) in the DDDR mode and level below a
certain percentage (80%) in the VVIR mode. These results
imply that the risk of HFH in the DDDR mode does not
increase with further increases in Cum%VP ⬎40%, but this
risk might be reduced to ⬇2% if ventricular pacing is
minimized. In contrast, the relative risk of HFH in the VVIR
mode cannot be reduced regardless of minimization of
ventricular pacing, and this risk is increased by as much as
2.5-fold when Cum%VP exceeds 80%.
Ventricular pacing was also associated with an increased
risk of AF. The best models demonstrated a linearly increasing risk of AF with Cum%VP in DDDR and VVIR modes up
to ⬇80% to 85%. The magnitude of increased risk was ⬇1%
for each 1% increase in Cum%VP and was similar between
pacing modes. This increased risk of AF associated with
increased Cum%VP in both modes persisted when the models
were adjusted for all other known baseline predictors of AF in
the study population.
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June 17, 2003
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Figure 3. Kaplan-Meier rates for freedom from first documented
incidence of atrial fibrillation by percent ventricular paced during
the first 30 days. a, DDDR mode; b, VVIR mode.
The reduction in heart failure and AF in atrial versus
ventricular pacing for SND has been attributed to the physiological benefit of maintaining AV synchrony during pacing.9
Long-term asynchronous ventricular pacing causes atrial
electrical remodeling and increased atrial diameters resembling that associated with chronic AF that are reversible with
restoration of AV synchrony.10,11
However, despite maintenance of AV synchrony, similar
benefits of dual-chamber pacing versus ventricular pacing
have been difficult to demonstrate in clinical trials. The
PAcemaker Selection in the Elderly (PASE) Trial3 showed a
trend toward improved quality of life and fewer clinical end
points (AF and HFH) among patients with SND treated with
DDDR versus VVIR pacing. The Canadian Trial Of Physiologic Pacing (CTOPP) reported a modest reduction of AF
among patients with any diagnosis (heart block, SND) treated
with DDDR versus VVIR pacing.2 MOST demonstrated
modest reductions in HFH and AF with DDDR versus VVIR
pacing in SND.1
Though DDDR pacing maintains a physiological AV
relation compared with ventricular pacing, this may come at
the cost of a normal ventricular activation sequence compared
with atrial pacing. The results of the present study strongly
suggest that the discrepancy between the relative benefits of
atrial compared with dual-chamber pacing in SND is due to
adverse effects of asynchronous electrical activation of the
left ventricle imposed by right ventricular apical pacing.
Right ventricular apical pacing produces a left ventricular
electrical activation sequence resembling left bundle-branch
block.12 The resulting alteration in mechanical activation may
result in impaired hemodynamic performance13,14 and mitral
regurgitation.15 Right ventricular apical pacing causes
chronic changes in regional myocardial perfusion,16 cellular
structure,17,18 and ventricular geometry19 that may impair
ventricular performance. The increased incidences of HFH
and AF observed in the more frequently ventricular paced
patients in the present study possibly relate to ventricular
desynchronization.
The adverse effect of ventricular pacing on heart failure
was modest, reflecting the fact that the vast majority of
patients had normal left ventricular function and no prior
history of symptomatic heart failure at baseline. It is possible
that the impact of forced ventricular desynchronization during DDDR pacing on patients with reduced ventricular
function and heart failure would be more dramatic. One
retrospective study reported symptomatic deterioration in
heart failure after institution of ventricular pacing in the
DDDR mode among ICD patients.20
Our results have potentially important clinical implications. The majority of patients with SND who receive
pacemakers or ICDs, including those with heart failure and
reduced ventricular function, have a normal ventricular activation sequence reflected in QRS duration ⬍120 ms. DDDR
pacing typically utilizes AV delays in the range of 120 to 200
ms that result in a high percentage of ventricular pacing
during normal operation. Ventricular desynchronization
caused by right ventricular apical pacing in the DDDR mode
may increase the risk of heart failure and AF, particularly
when imposed on the failing left ventricle. Such risks may be
reduced by minimal ventricular pacing strategies that preserve the normal ventricular activation sequence as much as
possible.
Study Limitations
This study does not demonstrate a definitive link between
ventricular desynchronization imposed by ventricular pacing
in the DDDR mode and HFH and AF. We did not measure
indexes of left ventricular performance over time or paced
QRS durations. It is possible that ventricular fusion or
pseudofusion occurred in some patients. Theoretically, however, this would have only weakened the association of
ventricular pacing with adverse outcomes. Prospective, randomized trials comparing conventional DDDR pacing, new
dual-chamber minimal ventricular pacing techniques that
promote intrinsic AV nodal conduction and preserve normal
ventricular activation,21 and perhaps cardiac resynchronization therapy in patients with AV block are necessary to
confirm these preliminary observations.
Conclusions
Our study suggests that ventricular desynchronization imposed by right ventricular apical pacing even when AV
synchrony is preserved increases the risk of heart failure and
AF in patients with SND and normal baseline QRS duration.
Further research is necessary to clarify the role of “electrical
unloading” of the left ventricle using minimal ventricular
pacing strategies in SND and normal QRS duration, particu-
Sweeney et al
Effect of Ventricular Pacing on Heart Failure and AF
larly among patients with reduced ventricular function and
symptomatic heart failure.
11.
Acknowledgments
This study was supported by grants U01-HL-49804 (G.A.L.) and
U01-HL-53973 (K.L.L.) from the National Heart, Lung, and Blood
Institute of the National Institutes of Health.
12.
13.
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for the MOde Selection Trial (MOST) Investigators
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Circulation. 2003;107:2932-2937; originally published online June 2, 2003;
doi: 10.1161/01.CIR.0000072769.17295.B1
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