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CLINICAL RESEARCH
Europace
doi:10.1093/europace/euu259
Department of Cardiology, Aberdeen Royal Infirmary/University of Aberdeen, Aberdeen AB25 2ZN, UK; and 2The George Institute for Global Health, University of Sydney, Australia
Aims
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Cardiac resynchronization therapy (CRT) Right ventricular outflow tract pacing Heart failure Left ventricular
dyssynchrony Left ventricular systolic function
Introduction
Cardiac resynchronization therapy (CRT) is an effective treatment in
patients with refractory heart failure due to severe left ventricular
(LV) systolic impairment in the presence of left bundle branch
block (LBBB).1 It improves the quality of life and prolongs survival.2 5 Cardiac resynchronization therapy is, therefore, recommended in international guidelines for appropriate patients with
heart failure6,7 and used extensively in clinical practice.8 Despite
* Corresponding author. Tel: +44 1224 550761; fax: +44 122 550692. E-mail address: h.alhous@abdn.ac.uk
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: journals.permissions@oup.com.
To compare the effects on left ventricular (LV) function of right ventricular (RV) septal pacing vs. cardiac resynchronization therapy (CRT) in patients with an indication for the latter. Cardiac resynchronization therapy is an effective therapy in
patients with drug-refractory heart failure. Despite advances in implantation techniques, LV lead placement can be impossible in up to 10% of cases. We, therefore, assessed the effects of RV septal pacing from mid septum (RVmIVS)
and outflow tract (RVOT) on cardiac performance, in comparison with CRT.
.....................................................................................................................................................................................
Methods
Twenty-two patients scheduled for CRT underwent dual-chamber temporary pacing. The ventricular lead was placed at
the RV apex (RVA), RVmIVS, and RVOT in random order. Comprehensive echocardiography was performed in a baseline
and results
AAI mode and then at each RV position in dual chamber pacemaker function (D pacing, D sensing, D dual responses)
mode and repeated on the next day following CRT implantation. Right ventricular apex pacing did not change any of
the assessed echocardiography parameters. Both RVmIVS and RVOT pacing increased LV ejection fraction (EF):
29 + 7% at baseline vs. 32 + 6% (P 0.02) and 32 + 5% (P 0.04) with RVmIVS and RVOT pacing, respectively. Similarly, the dyssynchrony index (Ts-SD) decreased: 50 + 19 ms at baseline vs. 39 + 17 ms (P 0.04) and 37 + 17 ms
(P 0.006) with RVmIVS and RVOT pacing, respectively. Cardiac resynchronization therapy further improved LVEF
and Ts-SD to 36 + 7% and 34 + 15 ms, respectively, however, only LVEF was significantly higher compared with
RVmIVS and RVOT pacing (P 0.03 and P 0.01 respectively). There were no significant differences in either LVEF
or Ts-SD between RVmIVS and RVOT.
.....................................................................................................................................................................................
Conclusion
Right ventricular septal pacing from mid septum or RVOT pacing improves LVEF and LV synchrony in CRT candidates.
Further improvement in LVEF was achieved by CRT, which remains the gold standard therapy in these patients.
However, RV septal pacing is worthy of further study as an alternative strategy when LV lead implantation fails.
Page 2 of 7
Whats new?
The effects of right ventricular (RV) septal pacing from RV mid
septum and RV outflow tract on LV function and dyssynchrony
in patients with indication for CRT (cardiac resynchronization
therapy).
Right ventricular septal pacing as an alternative to failed left
ventricular lead in patients with indication for CRT.
Methods
Study population
Patients who were scheduled to undergo conventional CRT implantation
were recruited to the study. Patients with a current atrial tachyarrhythmia
were excluded. The temporary pacing protocol was performed 4
weeks prior to the date of CRT implantation. The study was approved
by the Grampian Research Ethics Committee and informed consent
was obtained.
Pacing procedure
Dual-chamber temporary pacing
Temporary pacing was performed in a sterile manner via the right femoral
vein using two intra-cardiac electrical catheters (TORQRTM , Medtronic).
Under fluoroscopic guidance one catheter was placed in the high right
atrium; the second catheter was then placed in the RV. Temporary
atrial pacing (AAI) was established at 10 beats per minute (b.p.m.)
above the baseline sinus rate to ensure constant pacing throughout
the study.29 Temporary dual chamber pacemaker function (D pacing, D
sensing, D dual responses) (DDD) pacing was subsequently commenced
at the established atrial rate. The pacing rate was kept the same throughout the study at all RV sites. Atrio-ventricular (AV) delay was optimized
according to the trans-mitral pulse-wave Doppler echocardiographic
method.31 The ventricular pacing catheter was placed in random order
at three RV pacing sites: RV apex (RVA), RVmIVS and RVOT. Ventricular
pacing lead positions were confirmed by both fluoroscopy in both left anterior oblique and right anterior oblique views (to ensure the septum, not
the free wall was being paced) and electrocardiogram (ECG) characteristics.32,33 Pacing was carried out at twice diastolic threshold. Direct
His bundle capture was avoided. A full study protocol (detailed
Electrocardiography
A 12-lead surface ECG was performed prior to the study, during AAI
pacing, at each RV pacing site studied, and post CRT. QRS duration was
calculated using the first to the last sharp vector crossing the isoelectric
line in all leads. The mean of these values was used for statistical analysis.
Echocardiography
A detailed trans-thoracic echocardiogram was performed during AAI
pacing, during DDD pacing at each RV pacing site, and on the day following CRT device implantation. Subjects were paced for 10 min at each RV
pacing site prior to echocardiographic assessment. Images were obtained
using a 3.5 MHz phased-array transducer and a Vivid 7 echocardiography
machine (General Electric Healthcare). For all echocardiography data, at
least three consecutive paced cardiac cycles were stored in cine-loop
format for off-line analysis (EchoPAC, General Electric Healthcare). All
echocardiographic variables were measured in triplicate from three
different paced beats and the average value was calculated and used for
statistical analysis.
Left ventricular ejection fraction was measured using Simpsons
bi-plane method and cardiac output calculated.35 Left ventricular diastolic function was assessed from the mitral inflow in the apical four-chamber
view using pulse-wave Doppler.36 Systolic and diastolic function was also
evaluated using colour tissue Doppler imaging (TDI) to measure mitral
annular and myocardial velocities.37
Intra-ventricular dyssynchrony (LV dyssynchrony): TDI was used to
assess longitudinal LV dyssynchrony. Myocardial velocity curves were
constructed from the three standard TDI apical views and the peak sustained myocardial systolic velocity (during the ejection phase) (Sm) for
each of the 12-LV segments was identified. The time-to-peak Sm (Ts)
was measured with reference to the onset of the QRS complex.31,38
From these measurements, a variety of previously described dyssynchrony parameters were derived. These included the difference in Ts
between the basal septum and the lateral wall (septal-to-lateral delay),
where a difference of 65 ms is a widely used indicator of LV dyssynchrony, and the standard deviation for Ts among all 12 basal and
mid-LV segments (the dyssynchrony index), where a cut-off value of
32.6 ms is suggested.38,39
Inter-ventricular dyssynchrony: The time from the Q-wave on the
ECG to semi-lunar valve opening was evaluated using pulsed-wave
Doppler of the LV outflow tract in the apical five-chamber view and
the RVOT in the short axis parasternal view. An inter-ventricular
CRT;17,18 however, these benefits come at the expense of perioperative complications associated with the use of general anaesthesia in
patients with severe LV impairment.19 21 A more simple alternative
strategy to failed LV lead implantation could be achieved by percutaneous placement of the pacing lead at a site close to the LV such as the
RV outflow tract or RV mid septum. Right ventricular outflow tract
lead placement is a relatively simple procedure that is often used in
permanent pacing for bradyarrhythmias and can be carried out at
no additional risk.22 27 Furthermore, in patients who have bradycardia indications for pacing with concomitant heart failure, early studies
reported an improvement in LV ejection fraction (LVEF) and
New York Heart Association (NYHA) class with alternative RV
site pacing.28 30 In CRT candidates, however, it remains undetermined whether alternative RV site pacing may improve LV function.
The aim of the current study is to compare the effects of pacing
from the RV apex, RV mid septum (RVmIVS) and RVOT on LV synchrony and function with standard CRT.
M. H. A. Alhous et al.
Page 3 of 7
Statistical analysis
Continuous data are expressed as mean and standard deviation (SD)
where normally distributed and median with interquartile range (IQR)
were skewed. Non-parametric related data were compared using the
Wilcoxon signed-rank test. Analysis of variance also was conducted to
determine which of the paired comparisons differ significantly using
post-hoc multiple comparisons for observed means. Inter- and
intra-observer variability were determined using the Bland Altman
methods.40 Comparisons were made between each of the four pacing
sites and modes: AAI (baseline), RVmIVS, RVOT, and CRT.
Significance was established at a P-value of ,0.05. However, for
repeated comparisons a Bonferroni correction to control for a Type I
error was applied. All statistical calculations are undertaken using SPSS
version 20.
A total of 22 patients were recruited into the study. The study was
completed in all the patients. The pacing rate needed to achieve
Patients
(Total n 5 22)
................................................................................
Age (years), mean + SD
70 + 11
Male, n (%)
NYHA class
13 (59)
18 (82)
4 (18)
20/2
14 (64)
8 (36)
5 (23)
Hypertension, n (%)
8 (36)
7 (32)
2 (9)
5 (23)
Anaemia, n (%)
Hypothyroidism, n (%)
4 (18)
4 (18)
3 (14)
65 + 13
124 + 21
69 + 11
55 + 18
166 + 26
14 + 68
13 (59)
8 (36)
1 (5)
Pacing from any site in the RV did not change any of the LV diastolic
function parameters when compared with baseline (Table 2). There
were no significant differences in diastolic measurements between
CRT and baseline or between CRT and either RV septal pacing site.
Results
Characteristics
45 (23 69)
P = 0.008
P = 0.04
P = 0.02
P = 0.32
50
40
LVEF (%)
AAI, single atrial pacing; RVA, RV apex; RVmIVS, RV mid inter-ventricular septum; RVOT, RV outflow tract; CRT, cardiac resynchronization therapy; LVEF, LV ejection fraction; LVEDV, LV end diastolic volume; LVESV, LV end systolic volume; CO,
cardiac output; Sm, myocardial systolic velocity; E, E wave velocity; A wave velocity; DT, E wave deceleration time; Em, myocardial early diastolic velocity; cm/s, centimetre per second; ms, millisecond; SD, standard deviation.
0.44
0.43
0.75
0.31
0.05
0.60
0.89
0.74
31 (28 47)
36 (24 47)
32 (23 52)
0.73
40 (26 65)
0.30
0.44
0.23
0.30
0.20
0.72
0.51
0.51
0.21
0.26
0.88
0.64
250 + 73
1.1 + 0.7
1.0 + 0.5
184 + 53
188 + 50
1.1 + 0.5
0.9 + 0.4
DT (ms), mean + SD
184 + 65
1.1 + 0.7
179 + 67
2.6 + 0.7
Sm (cm/s), mean + SD
LV diastolic function
0.66
0.71
0.94
0.23
0.14
0.90
0.81
0.16
2.6 + 0.8
2.5 + 0.6
2.5 + 0.9
0.76
4.9 + 1.4
2.3 + 0.8
0.02
0.03
0.01
0.76
0.78
0.78
5.6 + 1.8
4.9 + 1.6
4.9 + 1.4
0.81
CO (l), mean + SD
4.8 + 1.4
0.26
0.12
0.12
0.43
0.56
0.37
132 + 53
142 + 53
142 + 51
150 + 40
146 + 41
LVESV (mL), mean + SD
0.83
0.01
0.57
0.67
0.03
0.008
0.61
0.65
0.04
0.02
0.74
0.86
0.32
36 + 7
204 + 66
207 + 68
32 + 5
32 + 6
206 + 62
207 + 47
28 + 7
29 + 7
205 + 52
LVEDV (mL), mean + SD
.............................................................................................................................................................................................................................................
CRT
RVOT
RVmIVS
LV systolic function
RVA
AAI
Pacing modes
Baseline
P-values
Pacing sites
.................................................................... .........................................................................................................................................
M. H. A. Alhous et al.
30
mean
20
10
AAI
RVA
RVmIVS RVOT
CRT
Discussion
In patients with standard indications for CRT, pacing from the
RVmIVS or RVOT significantly increased LVEF and reduced the
degree of intra- and inter-ventricular dyssynchrony compared with
baseline, with no significant difference between these two RV
pacing sites. However, CRT resulted in a further significant improvement in LVEF.
Prior studies
Previous studies have reported conflicting results with regard to the
effects of RV septal pacing in heart failure patients. Some groups29,30
have found an improvement in LV systolic function and heart failure
class with RV septal pacing but others41 43 report no improvement
in LVEF. However, these early studies were performed on heterogeneous groups of patients, many of them with atrial fibrillation and with
differing degrees of LV systolic dysfunction. More importantly, the
patients in these studies did not fulfil the standard criteria for CRT,
whereas in the current study accepted indications for CRT were
strictly adhered to.6,7 More recently, Vlay et al. 44 documented the
clinical response of 22 patients who met the standard criteria for
CRT but in whom standard LV pacing was not possible and RVOT
pacing was used instead. All patients had improved NYHA functional
class, reduced levels of cyanosis, dyspnoea, and improved exercise
tolerance.
The mechanism whereby RV septal pacing improves the synchrony
and force of LV contraction in CRT candidates may be explained by
the earlier activation of the proximal LV through the thinner part of
the upper septum: similar to the mechanism whereby RV septal
pacing is thought to reduce dyssynchrony when compared with
RVA pacing in patients requiring a permanent pacemaker for bradyarrhythmia.22
The current study demonstrates that pacing from either RV septal
site results in less dyssynchrony than RVA pacing and a higher LVEF. It
also suggests that pacing from either septal site has a similar impact on
traditional echocardiographic indices of cardiac performance or
more novel parameters, including Ts-SD and IVMD. Moreover,
there was no significant difference in QRSd between RVmIVS and
RVOT pacing sites. These findings may offer practical flexibility as
Table 2 Left ventricular systolic and diastolic function: changes in LVEF with different RV pacing sites and CRT
Page 4 of 7
Pacing sites
P values
Baseline
Pacing modes
AAI
RVA
...............................................................
.................................................
RVmIVS
RVOT
CRT
...............................................................................................................................................
..........................................................................
........................................
.............................................................................................................................................................................................................................................
Intra-ventricular dyssynchrony
Ts-SD (ms), mean + SD
50 + 19
43 + 14
39 + 17
37 + 17
34 + 15
0.12
0.04
0.006
0.002
0.17
0.17
0.91
155 + 58
133 + 50
118 + 51
110 + 44
104 + 41
0.14
0.002
0.01
0.002
0.20
0.35
0.57
56 + 45
56 + 37
42 + 40
27 + 23
41 + 33
1.00
0.46
0.01
0.03
0.94
0.15
0.38
35 + 19
27 + 21
27 + 21
20 + 16
0.09
0.003
0.01
0.002
0.38
0.23
0.47
Inter-ventricular dyssynchrony
IVMD (ms), mean + SD
48 + 29
AAI, single atrial pacing; RV, right ventricle; RVA, RV apex; RVmIVS, RV mid inter-ventricular septum; RVOT, RV outflow tract; CRT, cardiac resynchronization therapy; Ts-SD, dyssynchrony index; SLD, septal to lateral delay; Ts-12, maximum delay
between 12 LV segments (6 basal & 6 mid); IVMD, inter-ventricular mechanical delay; SD, standard deviation; ms, millisecond; n: number of patients.
(a)
(b)
Ts-SD (ms)
100
80
60
40
20
100
80
60
40
20
pacing sites.
P = 0.04
P = 0.006
CRT
CRT
Page 5 of 7
P = 0.002
P = 0.002
RVmIVS RVOT
P = 0.01
RVmIVS RVOT
P = 0.003
RVA
P = 0.09
RVA
P = 0.12
AAI
AAI
The effects of different pacing sites were assessed by echocardiography and this may not reflect clinical outcome. This was an acute
study and a longer term study would be useful to demonstrate a sustained response. The number of patients in this study was small and
larger studies to confirm our findings and explore clinical end
points should be considered.
IVMD (ms)
Table 3 Intra- & Inter-ventricular Dyssynchrony: changes in Ts-SD and IVMD with different RV pacing sites and CRT
Page 6 of 7
0.59
,0.001
AAI, atrial pacing; RV, right ventricle; RVA, RV apex; RVmIVS, RV mid inter-ventricular septum; RVOT, RV outflow tract; CRT, cardiac resynchronization therapy; QRSd, QRS duration.
,0.001
0.003
0.004
0.02
,0.001
144 + 20
178 + 19
180 + 22
196 + 25
166 + 26
.............................................................................................................................................................................................................................................
160
110
60
QRSd (ms),
mean + SD
AAI
RVA
RVmIVS
RVOT
CRT
RVA vs.
AAI
RVmIVS vs.
AAI
RVOT vs.
AAI
CRT vs.
AAI
RVmIVS vs.
CRT
RVOT vs.
CRT
RVmIVS vs.
RVOT
RVmIVS vs.
RVOT
RV septal pacing vs. CRT
Pacing sites vs. baseline
Baseline
Pacing modes
P values
.................................................................... ...........................................................................................................................................
Pacing sites
210
AAI
CRT
Conclusions
Cardiac resynchronization therapy is superior to either RV septal
pacing site and remains the gold standard. Nevertheless, these data
indicate that RV septal pacing from either site may be an option for
those patients in whom LV pacing is not possible for technical
reasons and is worthy of further study.
Conflict of interest: none declared.
References
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M. H. A. Alhous et al.
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