Download Influence of left ventricular lead position relative to scar location on

Europace (2014) 16, iv62–iv68
doi:10.1093/europace/euu231
SUPPLEMENT: ORIGINAL RESEARCH
Influence of left ventricular lead position relative
to scar location on response to cardiac
resynchronization therapy: a model study
Peter R. Huntjens 1, John Walmsley 1, Sylvain Ploux 2, Pierre Bordachar 2,
Frits W. Prinzen 3, Tammo Delhaas 1, and Joost Lumens 1,2*
1
Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, P.O. Box 616, 6229 ER Maastricht, The Netherlands;
Hôpital Cardiologique du Haut-Lévêque, IHU LIRYC, CHU de Bordeaux, Bordeaux, France; and 3Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht
University, Maastricht, The Netherlands
2
Received 30 July 2014; accepted after revision 2 August 2014
Aims
It is unclear how the position of the left ventricular (LV) lead relative to a scar affects the haemodynamic response in
patients with dyssynchronous heart failure receiving cardiac resynchronization therapy. We investigated this complex
interaction using a computational model.
.....................................................................................................................................................................................
Methods
The CircAdapt computational cardiovascular system model was used to simulate heart failure with left bundle branch
block (LBBB). Myocardial scar was induced in four different regions of the LV free wall (LVFW). We then simulated bivenand results
tricular pacing (BVP) in each heart, in which LV lead position was varied. The LV lead position leading to maximal acute
change in LV stroke volume (SV) was defined as optimal lead position. In LBBB without scar, SV increase was maximal
when pacing the LVFW region most distant from the septum. With a scar adjacent to the septum, maximal response
was achieved when pacing remote from both the septum and the scar. When the scar was located further from the
septum, the BVP-induced increase of SV was small. For all hearts, pacing from the optimal LV lead position resulted in
the most homogeneous distribution of local ventricular myofibre work and the largest increase in summed left and
right ventricular pump work.
.....................................................................................................................................................................................
Conclusions
These computer simulations suggest that, in hearts with LBBB and scar, the optimal LV lead position is a compromise
between a position distant from the scar and from the septum. In infarcted hearts, the best haemodynamic effect is
achieved when electromechanical resynchronization of the remaining viable myocardium is most effective.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Haemodynamics † Optimization † Heart failure † Biventricular pacing † Computer model
Introduction
Cardiac resynchronization therapy (CRT) is recommended for
patients with moderate-to-severe heart failure, decreased left ventricular ejection fraction (LVEF ,35%), and widened QRS complex
(≥120 ms) preferentially with left bundle branch block (LBBB)
morphology on the 12-lead electrocardiogram.1 Cardiac resynchronization therapy has been shown to improve heart failure symptoms,
cardiac pump function, and survival rate of these patients.2,3 It is
believed that CRT improves cardiac pump function by resynchronization of left ventricular (LV) and right ventricular (RV) electrical activation, making myocardial contraction and relaxation more
uniform throughout the ventricular walls. Yet, approximately
one-third of the patients fail to benefit from CRT.2
Suboptimal LV lead positioning and regional myocardial scarring
are two factors believed to be associated with nonresponse to
CRT.4,5 Several clinical studies have shown that long-term CRT response is larger in patients with a non-ischaemic aetiology than in
patients with an ischaemic aetiology of heart failure,6,7 and that size
and severity of the scarred region were inversely related to CRT response.8 Nevertheless, these studies also demonstrated that ischaemic cardiomyopathy does not preclude a positive response to CRT.
Moreover, it has been suggested that location of the scar is an important determinant of CRT response.9 The site of optimal LV lead
* Corresponding author. Tel: +31 43 388 16 66; fax: +31 43 388 1725. E-mail address: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
iv63
Optimizing lead position in dyssynchronous hearts with scar
What’s new?
† Computer simulations reveal that in hearts with left bundle
branch block (LBBB) and scar in the left ventricular (LV)
wall, optimal LV lead placement for biventricular pacing for
acute haemodynamic response is a compromise between distance from the scar and distance from the septum.
† In LBBB hearts with or without scar optimal haemodynamic
effect coincides with the most synchronous activation of the
remaining viable LV myocardium and the most homogeneous
distribution of regional myofibre work.
shown in Figure 1B, resulting in a total ventricular activation time of
135 ms.5,15 Activation delay of a single segment, as illustrated in Figure 1
(B and C), represents the average time delay of onset activation in the
midwall region of the segment. Heart rate was set to 75 b.p.m.2 Circulating blood volume and peripheral vascular resistance of the systemic circulation were adjusted so that cardiac output (CO) and mean arterial
pressure equalled 3.8 L/min20 and 84 mmHg,2 respectively, representing
homoeostatic pressure-flow regulation. The resulting values of circulating blood volume and peripheral vascular resistance were maintained
during all other simulations. Global myocardial failure was simulated by
decreasing myofibre contractility in all ventricular segments to 60% of
its normal value so that LVEF was reduced to 34%.
Simulation of myocardial scar
position has been shown to vary among patients with ischaemic cardiomyopathy.5,10 Lead placement in scarred regions is associated
with a greater risk of mortality and morbidity than lead placement
in viable tissue.11 In addition, animal experimental data suggest that
acute haemodynamic response to CRT depends more critically on
LV lead position in hearts with myocardial infarction than in noninfarcted hearts.9,12 However, the exact relation between the
location of myocardial scar, the position of the LV pacing lead, and
the response to CRT is poorly understood.
In this study, we investigated the effects of LV lead position relative
to scar location on acute response to biventricular pacing (BVP),
using the CircAdapt computational model of the human cardiovascular system.13,14 Simulations of BVP with different LV lead positions in
hearts with and without myocardial scar were performed to obtain
more insight into the working mechanism of CRT.
Methods
Model design
The CircAdapt model of the heart and circulation13,14 enables realistic
beat-to-beat simulation of cardiovascular mechanics and haemodynamics under a wide variety of (patho-)physiological circumstances (www.
circadapt.org). CircAdapt consists of several module types, including
cardiac walls, cardiac valves, large blood vessels, systemic and pulmonary
peripheral vasculature, the pericardium and local cardiac tissue
mechanics (Figure 1A). The ventricles consist of three myocardial walls,
i.e. the LV free wall (LVFW), the interventricular septum (SEPT), and
the RV free wall (RVFW). These ventricular walls are mechanically
coupled at their junction by equilibrium of tensile forces, giving mechanical ventricular interaction (16). Global LV and RV pump mechanics are
related to myofibre mechanics in the three ventricular walls by the principle of conservation of energy. As described previously by Lumens
et al.,15 each cardiac wall was subdivided into mechanically coupled segments to enable simulation of local inhomogeneities in myocardial tissue
properties (onset time of activation, contractility, and passive stiffness).
Simulation of dyssynchronous heart failure
Starting from a reference simulation representing the normal adult heart
and circulation,16 a simulation of a failing heart with LBBB was obtained as
described previously.15 Briefly, an LBBB-like pattern of mechanical activation in the ventricles is modelled by activating the centre of the RV free
wall after a fixed delay of 220 ms. Earliest activation of a septal segment
occurred 30 ms later, mimicking slow transseptal activation.17 – 19 Activation then spreads from segment to segment with a delay of 15 ms, as
Using the simulation of the failing heart with LBBB as a starting point, myocardial scar was induced by reducing myofibre contractility in three
adjacent ventricular segments further from 60 to 10% of the normal contractility value, and by increasing passive stiffness in these three segments
to ten times its original value. In the two neighbouring segments, representing the border of the scar, contractility was reduced to 35% of its
normal value, while passive stiffness was increased five times. As shown
in Figure 1B, scar was induced at four different locations in the LVFW, beginning adjacent to the septum (SCAR1) and moving gradually towards
the centre of the LVFW (SCAR2 to SCAR4).
Simulations of cardiac resynchronization
therapy
Cardiac resynchronization therapy was simulated by simultaneously activating the centre of the RVFW and the SEPT, together with activation of
one of the 11 LVFW segments. For the LBBB heart with no scar, this BVP
protocol resulted in 11 different BVP simulations (Figure 1C, left). In contrast, only 8 different BVP simulations were performed in the LBBB hearts
with scar, as we assumed that scarred segments cannot be paced
(Figure 1C, right). In all simulations, intersegment activation delay
remained constant in viable, scar border, and scar tissue at 15 ms. As a
result, average activation of the LV myocardium during BVP varied
between 60 ms and 105 ms depending on both LV lead position and
the presence of LVFW scar. Additionally, the AV delay was reduced to
100 ms as in clinical CRT. All of the BVP pacing simulations were
assumed to lead to full ventricular capture, i.e. no fusion between intrinsic
ventricular conduction and pacing-induced activation.
Assessment of haemodynamic and mechanical
response to cardiac resynchronization therapy
Haemodynamic response to CRT at each pacing position was defined as
the percentage change of LV stroke volume (SV) relative to the baseline
simulation with the LBBB pattern of ventricular activation. The LV lead
position associated with the maximal BVP-induced acute change in LV
SV was defined as the optimal lead position. Dyssynchrony, defined as
the dispersion in onset time of electrical activation, was quantified by calculation of SD ATviable, the standard deviation of the activation delay of
all viable (non-scar and scar border) segments for both the RV and LV. For
each wall segment, local external myofibre work (in joule per cardiac
cycle, J/beat) was defined as the area enclosed by the Cauchy myofibre
stress-natural strain relation multiplied by the wall segment’s volume
(being 8.5 mL for all segments). Heterogeneity of local myofibre work
distribution, SD WORKsegmental, was quantified by the standard deviation
of all segments’ local myofibre work. Total ventricular pump work (in
joule per cardiac cycle, J/beat) was calculated as the sum of the areas
enclosed by both the LV and RV pressure– volume relations.
iv64
P.R. Huntjens et al.
A
Modules
CircAdapt
Systemic
circulation
RA
Pulmonary
circulation
PV
Vessel
Valve
LA
AV
Myocardial
walls
Wall junction
MV
TV
Resistance
LV
RV
Pericardium
Baseline
B
SCAR
no SCAR
1
15
45
120
LV
LV e e
fr
0 RV
45
30
Septum
15
3
R
ee
RV fr wall
2
SCA
4
135
120
Biventricular pacing
+ AV delay shortening
CRT
C
60
15
0
15
30
30
15
15
30
15
15
0
0
Variable pacing site
Border
45
30
60
45
15
30
30
15
15
0
30 45 45
45 30 15
60
Viable
45
SCAR
Fixed pacing site
0
30
60
90
120
Activation delay (ms)
Figure 1 Overview of the CircAdapt model and the simulation protocol. (A) shows the closed-loop circulation designed as a network of modules
representing atrial and ventricular cardiac walls subdivided into patches, blood vessels (arteries and veins), cardiac valves (AV, aortic valve; MV, mitral
valve; PV, pulmonary valve; TV, tricuspid valve), and the pulmonary and systemic peripheral vasculatures. (B) illustrates the baseline LBBB-like ventricular activation pattern in the heart without myocardial scar (no SCAR) and in a heart with SCAR close to the septum. Four different SCAR locations are simulated as indicated by numbers representing SCAR centres shifting from close to the septum (SCAR1) to remote from the septum
(SCAR4). Colours represent local activation delay with respect to the first activated ventricular segment. Per segment, this activation delay represents the tissue’s average time delay of onset activation. (C) shows examples of BVP-induced ventricular activation patterns (with arbitrary chosen LV
lead position) in the no SCAR and the SCAR1 hearts. Transparent red asterisks indicate all other potential LV lead positions. LBBB, left bundle branch
block; CRT, cardiac resynchronization therapy; LA, left atrium; LV, left ventricle; RA, right atrium; and RV, right ventricle. Adapted from Lumens
et al. 15
Results
Table 1 shows general LV haemodynamic function for all five baseline
LBBB simulations. Compared with the non-infarcted state, LV peak
systolic pressure and LV dP/dtmax were lower in the presence of
LV myocardial scar, while LV end-diastolic pressure (LVEDP) was
higher in the SCAR simulations.
Haemodynamic response to cardiac
resynchronization therapy: the
dyssynchronous failing heart without scar
Figure 2 shows pump function (SV), and CRT response, as percentage
change in SV, resulting from CRT when varying the LV lead position.
In the failing heart with LBBB and no scar, maximal increase of SV
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Optimizing lead position in dyssynchronous hearts with scar
(21%) was achieved when pacing any of the three LVFW segments
most distant from the septum. The least optimal LV pacing position (adjacent to the septum) was still associated with a 12% increase in SV.
from both the septum and the scar location, i.e. in the centre of the
remaining viable tissue. When the scar was located more distant
from the septum (Figure 2B, SCAR2 and SCAR3), the optimal LV
pacing position moved towards the viable tissue closer to the
septum. On average, the CRT-induced increase in SV was smaller
when the scar was located further away from the septum, as can be
appreciated from Figure 2B. In case of a heart with a scar most
distant from the septum (SCAR4), all available pacing positions
resulted in a similar and relatively small increase in SV (11%). In
Haemodynamic response to cardiac
resynchronization therapy: the
dyssynchronous failing heart with scar
Stroke volume increase due to BVP in a heart with a scar adjacent to
the septum (Figure 2B: SCAR1) was maximal when pacing was remote
Table 1 Simulated baseline LV haemodynamics
LBBB
.......................................................................................................................
no SCAR
SCAR1
SCAR2
SCAR3
SCAR4
...............................................................................................................................................................................
LV peak systolic pressure (mmHg)
106
91
93
95
96
LV dP/dtmax (mmHg/s)
773
611
650
685
697
10
34
14
30
13
31
13
31
13
32
LV end-diastolic pressure (mmHg)
LVEF (%)
no SCAR
SVbaseline = 51 ml
SCAR1
SVbaseline = 43 ml
Pump function: SV (ml)
e wall
fre
Viable
Border
Scar
Fixed pacing site
CRT response: DSV (%)
B
52
54
56
58
60
8
Optimal pacing site
Variable pacing site
10
12
14
16
18
20
22
24
LV
f
LV
RV
ree w
ptum
Se
e wall
fre
l
al
R
50
R
RV
V
48
SCA
LV
f
LV
46
SCAR4
SVbaseline = 46 ml
ree w
ptum
Se
V
44
SCAR3
SVbaseline = 45 ml
l
al
R
A
SCAR2
SVbaseline = 44 ml
DSV (%)
C 25
R = –0.99
p < 0.001
15
5
R = –1.00
p < 0.001
R = –0.98
p < 0.001
20
30
SD ATviable (ms)
20
30
SD ATviable (ms)
20
30
SD ATviable (ms)
R = –0.96
p < 0.001
20
30
SD ATviable (ms)
R = –0.98
p < 0.001
20
30
SD ATviable (ms)
Figure 2 Effects of CRT on SV and resynchronization of viable myocardial tissue. In (A), the colour of a LV free wall segment represents absolute
stroke volume (SV), during BVP with the LV lead positioned in that particular segment., in (B), the colours represent the percentage change in SV
relative to baseline (△SV), as a result of BVP with the LV lead positioned in that segment. Black circles indicate the optimal LV pacing position for that
heart as measured by maximal increase in SV. SVbaseline is the SV value in the non-paced baseline situation, i.e. left bundle branch block activation. The
lower (C) shows correlations between the standard deviation of delay in onset activation time of both RV and LV viable tissue (SD ATviable) and △SV.
Colours in circles represent △SV. Grey regions indicate scar, black dots border zone.
iv66
P.R. Huntjens et al.
general, BVP with optimal LV lead position led to a larger absolute SV
in the failing heart without scar than in the hearts with scar, as shown
in Figure 2A. For each heart, the relation between BVP-induced
haemodynamic response, in terms of DSV, and synchrony of activation, in terms of SD ATviable, is shown in Figure 2C. For each heart,
DSV was inversely related to SD ATviable. The maximal gain in resynchronization of the viable tissue and thus also in haemodynamic function that could be achieved by optimizing LV lead position was largest
in the no SCAR and SCAR1 hearts and smallest in the SCAR4 heart.
Mechanical response to cardiac
resynchronization therapy:
pacing-induced redistribution of local
myofibre work
To further investigate the link between local (dys)synchrony of ventricular activation and global ventricular pump function, we quantified
the distributions of local myofibre work (WORKsegmental ) over
the ventricular segments in all pacing simulations (Figure 3). The
relation between the standard deviation of WORKsegmental (SD
WORKsegmental ) and total ventricular pump work is shown in
Figure 3A. In all hearts, BVP with the LV lead at the optimal pacing
site, i.e. leading to maximal increase of total pump work, and thus
Discussion
Using a computational model of the human cardiovascular system
representing a failing heart with LBBB and myocardial scar, we have
Total pump vs segmental myofibre work
A
0.3
Best
no SCAR
Pump
workbaseline: 0.81 J/beat
D Pump work
(J/beat)
maximal SV, was associated with a more homogeneous distribution
of WORKsegmental. When applying BVP to a heart with a scar
located remote from the septum (SCAR4), all BVP simulations with
different LV lead positions led to similar values of SD WORKsegmental
(0.037 + 0.001 J/beat) and total ventricular pump work (0.78 +
0.01 J/beat, Figure 3A). Consequently, the increase of SV was almost
equal for all BVP simulations in the SCAR4 heart. As an example,
Figure 3B shows local myofibre work distributions for the SCAR1
heart during baseline (LBBB), and during BVP with LV lead positions
leading to largest (green panel) and smallest (red panel) increase in
SV. Biventricular pacing with optimal LV pacing position resulted in
the most effective resynchronization of the viable myocardial tissue
(SD ATviable decreased from 38 to 17 ms, Figure 2C). This resynchronization coincided with the largest BVP-induced decrease of SD
WORKsegmental and the largest increase in pump work compared
with baseline (Figure 3A, green arrow). The scarred segments made
very little contribution to the total amount of pump work (1% per
segment), since they were stiff and non-contractile.
R = –1
p < 0.001
SCAR1
0.59 J/beat
R = –0.97
p < 0.001
SCAR2
0.62 J/beat
SCAR3
0.65 J/beat
R = –0.98
p < 0.001
SCAR4
0.66 J/beat
R = –0.89
p < 0.005
R = –0.97
p < 0.001
0.2
Worst
0.1
0.04
0.06 0.02
0.04
0.06 0.02
0.04
0.06 0.02
0.04
0.06
0.02
0.04
0.06 0.02
SD worksegmental (J/beat) Sd worksegmental (J/beat) Sd worksegmental (J/beat) Sd worksegmental (J/beat) Sd worksegmental (J/beat)
Worksegmental (J/beat) –0.02
B
0
Worst response
Baseline
0.02
0.04
0.06
0.08
0.1
0.12
Best response
SCA
R
Viable
Border
SCAR
Fixed pacing site
Variable pacing site
Figure 3 Total pump work vs. distribution of segmental myofiber work. Correlation between increase in total pump work (DPump Work) and the
standard deviation of LV and RV segmental myofibre work (SD WORKsegmental ) during biventricular pacing (A). Arrows indicate the data points corresponding with the two example simulations of BVP in the SCAR1 heart resulting in best (green) and worst (red) CRT response for which myofibre
work per ventricular segment is shown (B).
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Optimizing lead position in dyssynchronous hearts with scar
evaluated how the position of the LV pacing lead interacts with scar
location in achieving acute response to BVP. The results indicate that
the largest improvement in LV pump function occurs when viable
myocardial tissue is maximally resynchronized. This is achieved by
positioning the LV lead as remote as possible from both the scar
and the septum. These results highlight the importance of LV
pacing lead positioning in CRT and may help to design clinical
studies on the most effective pacing site in patients with dyssynchronous heart failure and scar.
The finding that in the heart with LBBB without scar, pacing in a
relatively large area of the LVFW was associated with optimal or
near optimal haemodynamic response, corresponds to findings in
canine models of dyssynchronous heart failure by Helm et al. 12 and
Rademakers et al. 9 Derval et al. 21 found a wide variation of the
optimal LV lead position, but with significant effect at almost all sites.
It has been reported that pacing near or in the scar is associated
with a disproportionally worse outcome compared with any pacing
outside the scar or in hearts without scar.22 – 27 De Roest et al. 24
observed an improvement in cardiac pump function in hearts with
scarred regions, when placing the LV lead in viable tissue. However
they did not investigate the optimal LV lead location within the
viable tissue relative to scar location and the septum. Our simulations
indicate for the first time what the optimal location of a LV lead could
be in hearts with LBBB and scar. Patients with scar tissue may benefit
from CRT provided that the LV lead is positioned strategically, as also
is shown in both an electroanatomic mapping study5 and a recent
echocardiographic study.28 Spragg et al. 5 used electroanatomic
mapping to determine the influence of infarct location and LV endocardial pacing lead location on acute haemodynamic response.
Optimal pacing sites were located remote from scar regions and in
viable tissue, which is in accordance with our simulations results.
However, in the simulation with the scar most remote from the
septum (SCAR4), the increase in SV achieved by pacing was relatively
small compared with the response in the hearts with intermediate
scar locations, irrespective of LV lead positioning. This finding may
explain the observation that patients with lateral infarcts are poor
responders to CRT.22,29 We excluded the possibility of pacing
within the scar as this is against current clinical practice due to
limited capture of the remaining viable LV myocardium caused by
slow conduction30 and limited capture of the scar due to high
pacing thresholds.
It is known from experimental animal studies 31,32 that ventricular
pacing redistributes mechanical myofibre work in the LV myocardium so that the latest activated region generates the highest
amount of mechanical work, and the earliest activated region generates nearly no mechanical work or even dissipates work. In a more
recent study,15 we demonstrated that pump work performed by
both RV and LV plays an important role in the explanation of haemodynamic response to CRT. A further insight resulting from our
current study is that the pacing-induced redistribution of regional
myofibre work also plays an important role in the optimization of
LV lead positioning relative to infarct location in ischaemic heart
failure. Our simulation data suggest that the optimal LV lead position
is a compromise between the position most distant from the scarred
region and the position most distant from the RV lead. This balanced
position will lead to the most synchronous activation of the viable
tissue and, hence, the most homogeneous distribution of mechanical
myofibre work in the ventricular walls, leading to best haemodynamic
response to CRT. In a heart without myocardial scar, this reasoning
automatically guides the optimal position to the tissue most distant
from the RV lead, being the lateral wall when LV myocardial conduction velocity is homogeneous.
Clinical implications and future
perspectives
In general, our simulation data highlight the need for proper LV lead
positioning relative to both scar and the interventricular septum in
order to obtain optimal haemodynamic response to CRT. These
novel insights obtained from model simulations may be useful in
the design of prospective clinical and experimental studies. In clinical
practice, LV lead placement may be limited by the accessibility and
anatomy of epicardial coronary veins and by the risk of phrenic
nerve stimulation. However, novel developments such as quadripolar leads, endocardial pacing, and wireless pacing may increase the
chance of positioning the LV lead in the preferred region.9,33 – 35 To
determine the optimal LV lead position in an individual patient for
optimal CRT response, we must also take into account the heterogeneity in the pathological and clinical status present in patients.
We believe that computational modelling will become more important in understanding the role of different factors related to CRT
response and their complex interactions, and that it can potentially
be used in individualized patient selection.
Limitations
In these simulation, dyssynchrony-induced structural and electrophysiological remodelling have not been taken into account.36 Furthermore, we only considered acute response to CRT, and did not
consider resynchronization-induced remodelling which may influence long-term response.7 The Frank-Starling mechanism by which
myocytes increase contractility with sarcomere length is not
limited in our model, which may cause non-physiological contractility
at high levels of pre-stretch. Scar-related local heterogeneities in conduction velocity, which can influence CRT response,30 have not been
considered. Our model cannot be used to evaluate arrhythmic risk
that may arise from pacing near or in the scar region, as it does not
include a mathematical description of cellular electrophysiology.
The highly simplified description of ventricular geometry in the CircAdapt model did not allow investigation of the potential role of
transmural and apex-to-base propagation of activation. Geometrically more complex models, such as the one presented by Constantino
et al.,37 can be used to gain more insight into the effects of transmural
and apex-to-base conduction on response to CRT in infarcted hearts.
Conclusions
Computer simulations show that the largest haemodynamic improvement following CRT can be obtained by activating the viable
myocardial tissue as synchronously as possible. Hence, in a failing
heart with LBBB and no scar, one should target the LV myocardium
most distant from the RV lead for LV lead positioning. In the presence
of LV scar, however, the LV lead should be placed in a balanced position remote from both the scar and the RV lead.
iv68
Conflict of interest: none declared.
Funding
J.L. received a grant within the framework of the Dr E. Dekker program of
the Dutch Heart Foundation (NHS-2012T010). S.P. and P.B. were supported by the French Government, Agence National de la Recherche
au titre du programme Investissements d’Avenir (ANR-10-IAHU-04).
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