Download Effects of right ventricular pacing on left ventricular ejection fraction

Acta Cardiol 2012; 67(5): 577-582
577
doi: 10.2143/AC.67.5.2174133
Effects of right ventricular pacing on left ventricular ejection
fraction in a pacemaker clinic
Richard KOBZA1, MD; Andreas W. SCHOENENBERGER2, MD; Paul ERNE1, MD
1
Division of Cardiology, Luzerner Kantonsspital, Luzern, Switzerland; 2Division of Geriatrics, Department of General Internal Medicine,
Inselspital, Bern University Hospital, and University of Bern, Switzerland.
Background The aim of this study was to evaluate whether a change of left ventricular ejection fraction (LVEF) depending on percentage of
right ventricular pacing is found in a real-life setting of a pacemaker clinic.
Methods and results
269 patients with either a pacemaker or an ICD and who are regularly followed at the pacemaker clinic of the Luzerner
Kantonsspital participated in the study. We tested whether LVEF measured by echocardiography between the first measurement at the time of the pacemaker implantation and the last measurement at the time of the last pacemaker control is dependent on the extent of ventricular pacing. Mean follow-up
was 3.9 ± 2.9 years. Mean LVEF most significantly decreased in the group of patients with baseline LVEF ≥ 45% and an extent of right ventricular pacing
≥ 66% (from 57.6 ± 7.2% to 53.1 ± 10.2%, P < 0.001). In patients with an extent of right ventricular pacing < 66% no decrease of LVEF was observed.
Analysis of variance showed that LVEF decrease between the first measurement at the time of the pacemaker implantation and the last measurement at
the time of the last pacemaker control was dependent on the extent of right ventricular pacing, even if other factors such as age, gender and previous
myocardial infarction are incorporated in the analysis.
Conclusion
Keywords
In a real-life population of a pacemaker clinic right ventricular pacing was associated with a decrease in LVEF.
Right ventricular pacing – left ventricular ejection fraction – heart failure – resynchronization therapy – echocardiography.
Pacing from the apex of the right ventricle (RV) is
considered not optimal, as it provides a non-physiologic
asynchronous contraction, which results in a decrease
in cardiac performance1-4. Sweeny et al. had investigated
the effect of pacing-induced ventricular desynchronization in patients with normal baseline QRS duration.
They demonstrated that ventricular desynchronization
imposed by ventricular pacing increases the risk of heart
failure hospitalization in patients with sinus node dysfunction with normal baseline QRS duration, even when
AV synchrony was preserved5. Puggioni et al. have
shown that rhythm regularization achieved with AV
junction ablation improves ejection fraction (EF) with
Address for correspondence:
Paul Erne, M.D., Division of Cardiology, Luzerner Kantonsspital
6000 Luzern 16, Switzerland. E-mail: [email protected]
Received 31 January 2012; revision accepted for publication
25 April 2012.
both right ventricular (RV) and left ventricular (LV)
pacing and that LV pacing gives an additive modest but
favourable haemodynamic effect, as judged by a further
increase of EF6. Chan et al. found left ventricular adverse
remodelling and deterioration of systolic function in
patients with bradycardia and preserved LVEF7. Longterm right ventricular pacing alone does not appear to
be associated with development of heart failure, ventricular function deterioration or reduced survival in
antinuclear antibody negative isolated congenital atrioventricular block patients8,9.
The aim of the present study was to evaluate whether
a decline of EF depending on percentage of right ventricular pacing is found in a population of a pacemaker
clinic.
METHODS
Study population
All patients with a pacemaker or ICD and who are
regularly followed at the pacemaker clinic of the Luzerner
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Kantonsspital were eligible for the study. Patients were
included in the study if an echocardiographic study was
available within a 1.5-year interval before or after the
date of the pacemaker implantation. At entry into the
study clinical characteristics were collected through
medical record review and interrogation of the patients.
1068 patients were regularly followed at the pacemaker
clinic, 743 for an implanted pacemaker and 325 for an
ICD, respectively. 61 patients with biventricular pacing
were excluded. The study population finally consisted
of 269 patients. 799 patients did not fulfill the inclusion
criteria, mostly due to missing echocardiographic studies. The study population was further divided into
2 subgroups: subjects having right ventricular pacing in
≥ 66% of the time and those with < 66% pacing, respectively. This cut-off point was chosen after analysing all
patients (figure 1) and with the aim to have a group with
patients who are paced most of the time. The study was
conducted in accordance with the Declaration of
Helsinki.
comparisons, the Student’s t-test was used after checking
for normal distribution; the Mann-Whitney rank-sum
test was used for non-normally distributed continuous
variables. Distributional differences between categorical
variables were assessed by a chi-square test and Fisher’s
exact test. Analysis of variance (ANOVA) was performed
to verify the independent association of right ventricular pacing and LVEF decrease. ANOVA was performed
as multivariable model including age, sex, occurrence
of a myocardial infarction during follow-up and time
between first and last LVEF measurement as independent factor variables. Data are presented as mean ± SD.
The continuous variables age and time between first and
last LVEF measurement were dichotomized at their
median values for ANOVA. For the reporting of ANOVA,
the F-ratio and the P-value are provided. For all statistical comparisons, a P value < 0.05 was considered significant.
RESULTS
Follow-up and measurements
At our pacemaker clinic, all patients are followed
bi-annually, or at least annually. At each follow-up visit,
they are monitored for angina pectoris, NYHA classification, syncope and other events such as myocardial
infarctions, operations, etc. Myocardial infarction was
defined as typical rise and gradual fall (troponin) or
more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis with at least one of the following: ischaemic symptoms; development of pathologic
Q waves on the ECG, ECG changes indicative of ischaemia (ST-segment elevation or depression), or coronary
artery intervention (e.g., coronary angioplasty)10. At the
last pacemaker follow-up, another echocardiographic
study was performed. LVEF was determined by conventional echocardiography (TTE) using the modified
Simpson method. Further echocardiographic measurements analysed included left ventricular end-diastolic
diameter (LVEDD), left ventricular end-systolic diameter and left ventricular end-diastolic volume (EDV).
Duration of follow-up was computed from the time
of the first echocardiographic study at the time of
implantation to the last echocardiographic study at the
time of a pacemaker interrogation. Cumulative atrial
and right ventricular pacing was registered in each pacemaker as the total number of paced beats in proportion
to the number of beats during the follow-up period.
Statistical analysis
Data were analysed using Stata software (Stata 11.2,
StataCorp LP, College Station, TX, USA). For two-group
Baseline characteristics of the 269 patients included
in the study are shown in table 1. Mean age was 71±
12 years with a range from 18.4 years to 90.8 years.
A dual-chamber pacemaker had been implanted in
234 (87%) patients and a single-chamber pacemaker in
35 (13%) patients, respectively. Most patients required
the pacemaker for atrio-ventricular block or for sick
sinus syndrome (table 1), a single-chamber pacemaker
was implanted in case of permanent atrial fibrillation.
In patients with LVEF < 45% significantly more patients
received the pacemaker in combination with an ICD.
Ventricular tachycardias were the indication for the
device implantation in most of these patients (summarized under “other” in table 1). Accordingly, in the group
with LVEF < 45% there were more patients with structural heart disease. In the group with LVEF ≥ 45% there
were significantly more patients with sick sinus syndrome.
Results of the baseline echocardiographic parameters
are provided in table 1. The baseline echocardiography
was performed with a median time of 6 days before
pacemaker implantation (with an interquartile range
from 33 days before implantation to the day on which
the pacemaker was implanted). The mean follow-up
duration from the baseline echocardiography to the last
echocardiographic follow-up was 3.9 ± 2.9 years. The
pacing mode at the last follow-up is shown in table 2.
At the last follow-up, 215 (80%) patients were in sinus
rhythm, 47 (17%) in atrial fibrillation and 7 (3%) presented without an intrinsic rhythm, respectively.
The mean LVEF of all subjects was 54.3 ± 11.3% at
the time of pacemaker implantation and showed a
Pacing and ejection fraction
Table 1 Baseline characteristics
Characteristic
Age (years)
Sex (male/female)
Body mass index (kg/m2)
All study participants
(n = 269)
Participants with LVEF < 45%
(n = 42)
Participants with LVEF ≥ 45%
(n = 227)
p value*
71.1 ± 12.2
67.8 ± 10.9
71.7 ± 12.3
0.06
180/89 (67%/33%)
30/12 (71%/29%)
150/77 (66%/34%)
27 ± 5
27 ± 4
27 ± 5
NYHA I
146 (54%)
12 (29%)
134 (59%)
NYHA II
100 (37%)
22 (52%)
78 (34%)
NYHA III
22 (8%)
7 (17%)
15 (7%)
1 (2%)
0 (0%)
0.50
0.86
Dyspnoea
1 (0.3%)
NYHA IV
<0.001
Indication for pacemaker or ICD
implantation†
AV block
118 (44%)
15 (36%)
103 (45%)
0.25
Sick sinus syndrome
110 (41%)
9 (21%)
101 (44%)
< 0.01
Atrial fibrillation
25 (9%)
2 (5%)
23 (10%)
0.39
Brady-tachy syndrome
18 (7%)
4 (10%)
14 (6%)
0.50
Other
23 (9%)
17 (40%)
6 (3%)
< 0.001
Ischaemic
56 (21%)
14 (33%)
42 (19%)
0.03
Valvular
43 (16%)
4 (10%)
39 (17%)
0.26
Hypertensive
36 (13%)
1 (2%)
35 (15%)
0.02
Dilated cardiomyopathy
11 (4%)
7 (17%)
4 (2%)
< 0.001
8 (3%)
2 (5%)
6 (3%)
0.36
Structural cardiopathy
Various
Echocardiographic parameters
LVEF, %
54.3 ± 11.3
34.0 ± 8.1
58.0 ± 7.0
< 0.001
EDV, ml
103.7 ± 44.6
149.2 ± 62.2
95.3 ± 34.8
< 0.001
LVEDD, mm
50.2 ± 7.8
56.5 ± 7.6
49.1 ± 7.3
< 0.001
LVESD, mm
34.4 ± 8.8
44.6 ± 8.8
32.6 ± 7.4
< 0.001
Abbreviations: AV: atrio-ventricular, EDV: end-diastolic volume, ICD: implantable cardioverter/defibrillator, LVEDD: left ventricular end-diastolic diameter, LVEF: left
ventricular ejection fraction, LVESD: left ventricular end-systolic diameter.
* p value for the comparison of patients with LVEF < 45% vs ≥ 45%.
† More than 1 indication per patient allowed.
Table 2 Pacing mode at last follow-up
All study participants
(n = 269)
Participants with LVEF < 45%
(n = 42)
Participants with LVEF ≥ 45%
(n = 227)
p value*
DDD
214 (80%)
31 (74%)
183 (81%)
0.40
Pacing mode
VVI
48 (18%)
9 (21%)
39 (17%)
VDD
6 (2%)
2 (5%)
4 (2%)
DDI
1 (0.4%)
0 (0%)
1 (0.4%)
* p value for the comparison of patients with LVEF < 45% vs ≥ 45%.
decrease to 52.0 ± 11.8% at the last follow-up (P = 0.02).
The course of the LVEF between first and last follow-up
significantly differed between different subgroups of
participants. Table 3 shows an overview of the changes
in LVEF for all study participants and participants with
a baseline LVEF < 45% or ≥ 45%. In study participants
with an LVEF < 45% no change in LVEF was found during follow-up, whereas in the group with LVEF ≥ 45% a
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Fig. 1 Change of left ventricular ejection fraction (y-axis)
according to the amount of ventricular pacing (%), x-axis: each
point representing one patient.
Fig. 2 Percentage of patients (y-axis) showing a decrease of LVEF
≥ 10%, when divided into four groups according to the amount of
ventricular pacing (=VP), x-axis.
decrease of LVEF from 57.6 ± 7.2% to 53.1 ± 10.2% was
documented in the subgroup with right ventricular pacing ≥ 66% (P < 0.001).
Figure 2 shows the percentage of patients showing a
decrease of LVEF of more than 10 percent divided into
four groups according to the amount of ventricular pacing. The highest proportion of patients with a LVEF
decrease of more than 10% was found in the group with
VP > 75%. In the group with right ventricular pacing
less than 25% there were more younger patients (mean
64.7 years compared to 71.1 years in the whole study
population) and more with ischaemic heart disease
(23.1% vs. 18.2% in the whole study population).
To document the independent association of right
ventricular pacing with the decrease in LVEF, ANOVA
was performed after adjustment for age, sex, occurrence
of a myocardial infarction during follow-up and time
between first and last LVEF measurement. Right ventricular pacing was significantly associated with the
LVEF decrease in all study participants (F-ratio 3.97,
P value 0.047) and in particular in patients with a baseline LVEF ≥ 45% (F-ratio 5.75, P-value 0.017). Of the
other variables in the model, only the occurrence of a
myocardial infarction was significantly associated with
a decrease in LVEF in all study participants (F-ratio
20.38, P-value < 0.001) and participants with a LVEF
≥ 45% (F-ratio 18.53, P-value < 0.001). The time between
first and last LVEF measurement showed an association
in patients with a LVEF ≥ 45% (F-ratio 4.35, P-value
0.038).
A sensitivity analysis was performed in the 142
patients who had the baseline LVEF measurement in the
2 weeks before or after the pacemaker implantation
(table 4). This analysis showed similar results in the
whole study population, namely that right ventricular
pacing was significantly associated with a decrease of
the LVEF.
DISCUSSION
The main finding of the study is that LVEF decrease
between the first measurement at the time of the pacemaker implantation and the last measurement at the
time of the last pacemaker control is dependent on the
extent of ventricular pacing, even if other factors such
as age, gender and previous myocardial infarction are
incorporated in the analysis.
The DAVID (Dual Chamber and VVI Implantable
Defibrillator) trial demonstrated that dual-chamber rate
responsive pacing at 70/min worsens the combined end
point of mortality and hospitalization for heart failure
compared with ventricular backup-only pacing at 40
beat/min11. A possible explanation was that altered ventricular activation from right ventricular pacing was
responsible for these maladaptive effects in the DAVID
trial. In the present study all patients of our pacemaker
clinic were eligible and therefore 84% of all patients
presented with an LVEF ≥ 45%. In these patients we
found a LVEF decrease only, if they presented with a
high amount (more than 66%) of ventricular pacing.
Again, a possible explanation may be the altered ventricular activation from right ventricular pacing. On the
other hand, the high amount of ventricular pacing may
be the expression of the underlying heart disease, which
is progressing and may explain the decrease of LVEF.
Pacing and ejection fraction
Table 3 The course of LVEF between baseline and last measurement in the two pacing groups (VP = ventricular pacing)
Baseline LVEF
Last LVEF
p value
All (n = 269)
54.3 ± 11.3
52.0 ± 11.8
0.02
Subgroup with VP < 66% (n = 85)
53.8 ± 12. 6
53.6 ± 12. 6
0.92
Subgroup with VP ≥ 66% (n = 184)
54.5 ± 10. 7
51.3 ± 11.3
< 0.01
All (n = 42)
34.0 ± 8.1
38.2 ± 11.1
0.05
Subgroup with VP < 66% (n = 18)
33.7 ± 8.9
37.2 ± 12.0
0.33
Subgroup with VP ≥ 66% (n = 24)
34.3 ± 7.6
38.9 ± 10.6
0.09
All (n = 227)
58.0 ± 7.0
54.6 ± 10.0
< 0.001
Subgroup with VP < 66% (n = 67)
59.2 ± 6.6
58.0 ± 8.6
Subgroup with VP ≥ 66% (n = 160)
57.6 ± 7.2
53.1 ± 10.2
All study participants
Participants with LVEF < 45%
Participants with LVEF ≥ 45%
0.37
< 0.001
Abbreviations: LVEF, left ventricular ejection fraction.
Table 4
Sensitivity analyses in patients who had the baseline LVEF measurement in the 2 weeks before or after the pacemaker implantation
Baseline LVEF
Last LVEF
p value
All study participants
All (n = 142)
55.7 ± 11.0
52.4 ± 10.7
0.009
Subgroup with VP < 66% (n = 38)
55.2 ± 12.6
54.3 ± 11.1
0.759
Subgroup with VP ≥ 66% (n = 104)
56.0 ± 10.4
51.6 ± 10.5
0.003
All (n = 19)
34.7 ± 8.0
41.6 ± 10.9
0.032
Subgroup with VP < 66% (n = 6)
31.7 ± 11.6
39.5 ± 14.6
0.328
Subgroup with VP ≥ 66% (n = 13)
36.1 ± 5.7
42.5 ± 9.2
0.042
All (n = 123)
59.0 ± 7.1
54.0 ± 9.7
< 0.001
Subgroup with VP < 66% (n = 32)
59.6 ± 6.5
57.1 ± 7.9
0.177
Subgroup with VP ≥ 66% (n = 91)
58.8 ± 7.3
52.9 ± 10.0
Participants with LVEF < 45%
Participants with LVEF ≥ 45%
However, the present study was not designed to answer
this question. The authors aimed to illustrate the course
of LVEF in a real-time setting of a pacemaker clinic
according to the amount of ventricular pacing. In contrast to the DAVID trial, we did not find a decrease of
LVEF in patients with LVEF < 45% at baseline. If only
patients with reduced EF and with more than 66% pacing were analysed the LVEF did not decrease during
follow-up. In contrast to the DAVID trial, we minimized
ventricular pacing in all our patients, being aware of the
possible detrimental effects of asynchronous ventricular
pacing. Therefore a possible explanation is, that in these
patients with impaired LVEF the pacemaker or ICD was
< 0.001
implanted as a part of an integral treatment concept that
aimed to treat the heart failure, in contrast to the DAVID
trial, where a uniform pacing mode for all patients was
selected. These findings are in concordance with the
DAVID II Trial, where atrial pacing was shown to be a
safe alternative when pacing was desired, but afforded
no clear advantage or disadvantage over a ventricular
pacing mode that minimized pacing altogether12.
In the group with LVEF ≥ 45% there were significantly more patients with sick sinus syndrome. This is
plausible, as sick sinus syndrome often is not an expression of structural heart disease. In these patients predominantly atrial pacing was necessary and optimal
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pacemaker programming minimized ventricular pacing.
Therefore this difference in the baseline characteristics
may not have influenced the results. 70% of the patients
with LVEF ≥ 45% had right ventricular pacing ≥ 66%.
Although this may be surprisingly high, it is in concordance with previous data13.
In selected patients left ventricular adverse remodelling and deterioration of systolic function due to RV
pacing may be prevented by biventricular pacing7.
Study limitations
One limitation of this retrospective study is the highly
selective population although this was mainly due to
lacking data at the baseline (of the 1068 screened patients
only 269 patients had a baseline LV function evaluation).
Another major limitation is the measurement of the LV
function by echocardiography, known to have an interand intraobserver variability (even with the modified
Simpson method)14. Due to the retrospective design of
the study measurement of LVEF was allowed within a
period of 18 months before or after pacemaker implantation, therefore other clinical factors may have influenced the LVEF. However, due to the regular follow-up
in all patients in our pacemaker clinic, factors that may
have influenced the LVEF, such as a myocardial infarction, should all have been detected and therefore this
period of 18 months seems not to influence the results
of this study15,16. Furthermore, an ANOVA was performed as multivariable model including age, sex, occurrence of a myocardial infarction during follow-up and
time between first and last LVEF measurement as independent factor variables. Additionally, a sensitivity
analysis was performed in the patients who had the
baseline LVEF measurement in the 2 weeks before or
after the PM-implantation (table 4). This analysis
showed similar results in the overall study population.
CONCLUSION
Our study demonstrates that in a population of a
pacemaker clinic a decrease in LVEF was documented
most impressively in patients with a high incidence of
ventricular pacing, even if other factors such as age,
gender and previous myocardial infarction are incorporated in the analysis.
CONFLICT OF INTEREST: none.
REFERENCES
1. Ausubel K, Furman S. The pacemaker
syndrome. Ann Intern Med 1985; 103: 420-9.
2. Auricchio A, Moccetti T. Electronic cardiac
medicine: present and future opportunities.
Swiss Med Wkly 2010; 140: w13052.
3. Weishaupt D, Bremerich J, Duru F, Hoppe H,
Rizzo E, Votik P, Luechinger R. Pacemakers and
magnetic resonance imaging: Current status
and survey in Switzerland. Swiss Med Wkly
2011; 141: w13147.
4. Dabrowska-Kugacka A, Lewicka-Nowak E,
Rucinski P, Kozlowski D, Raczak G,
Kutarski A. Single-site Bachmann’s bundle
pacing is beneficial while coronary sinus
pacing results in echocardiographic right
heart pacemaker syndrome in
brady-tachycardia patients.
Circ J 2010; 74: 1308-15.
5. Sweeney MO, Hellkamp AS, Ellenbogen KA,
Greenspon AJ, Freedman RA, Lee KL,
Lamas GA. 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.
Circulation 2003;107: 2932-7.
6. Puggioni E, Brignole M, Gammage M,
Soldati E, Bongiorni MG, Simantirakis EN,
Vardas P, Gadler F, Bergfeldt L, Tomasi C,
Musso G, Gasparini G, Del Rosso A.
7.
8.
9.
10.
11.
Acute comparative effect of right and left
ventricular pacing in patients with
permanent atrial fibrillation.
J Am Coll Cardiol 2004; 43: 234-8.
Chan JY, Fang F, Zhang Q, Fung JW,
Razali O, Azlan H, Lam KH, Chan HC,
Yu CM. Biventricular pacing is superior to
right ventricular pacing in bradycardia
patients with preserved systolic function:
2-year results of the PACE trial.
Eur Heart J 2011; 32: 2533-40.
Sagar S, Shen WK, Asirvatham SJ, Cha YM,
Espinosa RE, Friedman PA, Hodge DO,
Munger TM, Porter CB, Rea RF, Hayes DL,
Jahangir A. Effect of long-term right
ventricular pacing in young adults with
structurally normal heart. Circulation 2010;
121: 1698-705.
Semmler D, Blank R, Rupprecht H.
Complete AV block in Lyme carditis:
an important differential diagnosis.
Clin Res Cardiol 2010; 99: 519-26.
Thygesen K, Alpert JS, White HD. Universal
definition of myocardial infarction.
Eur Heart J 2007; 28: 2525-38.
Wilkoff BL, Cook JR, Epstein AE, Greene HL,
Hallstrom AP, Hsia H, Kutalek SP, Sharma A.
Dual-chamber pacing or ventricular backup
pacing in patients with an implantable
defibrillator: the Dual Chamber and VVI
12.
13.
14.
15.
16.
Implantable Defibrillator (DAVID) Trial.
JAMA 2002; 288: 3115-23.
Wilkoff BL, Kudenchuk PJ, Buxton AE, Sharma
A, Cook JR, Bhandari AK, Biehl M, Tomassoni
G, Leonen A, Klevan LR, Hallstrom AP.
The DAVID (Dual Chamber and VVI
Implantable Defibrillator) II trial.
J Am Coll Cardiol 2009; 53: 872-80.
Steinbach M, Douchet MP, Bakouboula B,
Bronner F, Chauvin M. Outcome of patients
aged over 75 years who received a pacemaker
to treat sinus node dysfunction.
Arch Cardiovasc Dis 2011; 104: 89-96.
McGowan JH, Cleland JG. Reliability of
reporting left ventricular systolic function
by echocardiography: a systematic review of
3 methods. Am Heart J 2003; 146: 388-97.
Schoenenberger AW, Erne P, Ammann S,
Gillmann G, Kobza R, Stuck AE. Prediction
of arrhythmic events after myocardial
infarction based on signal-averaged
electrocardiogram and ejection fraction.
Pacing Clin Electrophysiol 2008; 31: 221-8.
Schoenenberger AW, Kobza R, Jamshidi P,
Zuber M, Abbate A, Stuck AE, Pfisterer M,
Erne P. Sudden cardiac death in patients with
silent myocardial ischemia after myocardial
infarction (from the Swiss Interventional
Study on Silent Ischemia Type II [SWISSI II]).
Am J Cardiol 2009; 104: 158-63.