Europace (2019) 0, 1–11 REVIEW

doi:10.1093/europace/euz126

Electrocardiographic optimization techniques

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in resynchronization therapy
Margarida Pujol-López1, Rodolfo San Antonio1,2, Lluı́s Mont 1,2,3*, Emilce Trucco4,
José Marı́a Tolosana1,2,3, Elena Arbelo1,2,3, Eduard Guasch1,2,3, Edwin Kevin Heist5,
and Jagmeet P. Singh5
1
Cardiology Department, Institut Clı́nic Cardiovascular (ICCV), Hospital Clı́nic, Universitat de Barcelona, Barcelona, Catalonia, Spain; 2Centro de Investigación Biomédica en Red
Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; 3Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain; 4Department of
Cardiology, Hospital Universitari Doctor Josep Trueta, Girona, Catalonia, Spain; and 5Cardiology Division, Cardiac Arrhythmia Service, Massachusetts General Hospital, Harvard
Medical School, Boston, MA, USA

Received 13 November 2018; editorial decision 2 April 2019; accepted 5 April 2019

Cardiac resynchronization therapy (CRT) is a cornerstone of therapy for patients with heart failure, reduced left ventricular (LV) ejection
fraction, and a wide QRS complex. However, not all patients respond to CRT: 30% of CRT implanted patients are currently considered
clinical non-responders and up to 40% do not achieve LV reverse remodelling. In order to achieve the best CRT response, appropriate
patient selection, device implantation, and programming are important factors. Optimization of CRT pacing intervals may improve results,
increasing the number of responders, and the magnitude of the response. Echocardiography is considered the reference method for
atrioventricular and interventricular (VV) intervals optimization but it is time-consuming, complex and it has a large interobserver and
intraobserver variability. Previous studies have linked QRS shortening to clinical response, echocardiographic improvement and favourable
prognosis. In this review, we describe the electrocardiographic optimization methods available: 12-lead electrocardiogram; fusion-
optimized intervals (FOI); intracardiac electrogram-based algorithms; and electrocardiographic imaging. Fusion-optimized intervals is an
electrocardiographic method of optimizing CRT based on QRS duration that combines fusion with intrinsic conduction. The FOI method
is feasible and fast, further reduces QRS duration, can be performed during implant, improves acute haemodynamic response, and achieves
greater LV remodelling compared with nominal programming of CRT.
...................................................................................................................................................................................................
Keywords Cardiac resynchronization therapy • Optimization • Fusion-optimized intervals • Reverse remodelling

However, only small randomized studies have demonstrated a bene-

Introduction
Not all patients respond to cardiac resynchronization therapy (CRT).
Up to 30% of CRT-implanted patients are clinical non-responders
and up to 40% do not achieve left ventricular (LV) reverse remodel-
ling.1 The cause of the non-response may be related to a combination
of factors: patient selection, device implantation, and programming.2–
4
Sustained and effective biventricular (BV) pacing is necessary to
achieve CRT response, aiming to achieve 98–100% of ventricular
pacing.5 Optimization of the CRT device to obtain the best resynch-
ronization may improve the response and eventually decrease the
proportion of non-responders.
Currently, there is a lack of consensus regarding CRT optimization
because insufficient data are available to support systematic optimiza-
tion of all patients. Several studies have demonstrated that optimizing
the atrioventricular (AV) and interventricular (VV) timing using echo-
cardiography can improve the acute haemodynamic response.6,7
fit of optimization [ECG Optimization of CRT: Evaluation of
Mid-term Response (BEST) NCT014395299].8 Regarding automated
optimization algorithms, AdaptivCRT algorithm demonstrated better
clinical outcomes compared with echocardiography optimization in a
secondary analysis.9 On the other hand, suboptimal programming of
the AV or VV delays may limit the response to CRT.2 For this reason,
evaluation and optimization of AV and VV delay is often recom-
mended in non-responders, although the benefit of this strategy to
improve CRT response requires further study.
Echocardiography has traditionally been considered the gold stan-
dard for CRT optimization.10 However, this method requires com-
plex adjustments that demand expertise and it is time-consuming.2
As a result, nearly 58% of the investigators surveyed do not optimize
the device at implantation, and nominal CRT programming is chosen
as the first option.11 Indeed, the SMART-AV trial has shown that
echocardiography is not better than out-of-the-box programming.12

* Corresponding author. Tel: þ34 932 271 778; fax: 934513045. Villarroel 170, Barcelona, Catalonia 08036, Spain. E-mail address: lmont@clinic.cat
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Published on behalf of the European Society of Cardiology. All rights reserved. V
Page 2 of 11
The electrocardiogram (ECG) seems therefore a potential alterna-
tive, especially since it is not observer dependent and can be easily
performed and repeated.
This review will examine the available knowledge about optimiza-
tion based on electrocardiographic measurements—an alternative to
echocardiography that offers an effective and feasible optimization
strategy.
Methods used to optimize cardiac
resynchronization therapy
Biventricular pacing devices are capable of sequential activation. It is
possible to optimize both the VV delay and the AV delay by modifying
their programming based on several methods13,14:
a. Echocardiography: mitral inflow (shortest AV delay without trunca-
tion of the A-wave, Iterative method, Ritter’s formula); LV outflow
tract velocity time integral; largest stroke volume; tissue Doppler im-
aging (TDI); LV M-mode (septal-posterior wall motion delay); strain
measurements.
b. Electrocardiographic QRS-based approach: 12-lead ECG; fusion-
optimized intervals (FOI).
c. Automated algorithms:
• Algorithms based on the intracardiac electrograms: QuickOpt,
SyncAV (St Jude Medical—Abbott); SmartDelay (Boston
Scientific); AdaptivCRT (Medtronic).
• Peak endocardial acceleration: Contractility sensor-guided opti-
mization (SonR-MicroPort).15 During cardiac contraction, the
myocardium generates mechanical vibrations. The SonR sensor
records an endocardial acceleration signal corresponding to
these vibrations.
• Finger photoplethysmography: Pulse pressure, Nexfin/finger
cuff. Nexfin combines a volume-clamp technique with an algo-
rithm to calculate stroke volume.
d. Body surface activation mapping.
e. Invasive haemodynamic measurements: LV dP/dt (first derivative of
LV pressure over time); stroke volume and stroke work derived from
pressure volume measurements.
f. Alternative techniques: Impedance cardiography, non-invasive radial
artery tonometry.
Electrocardiogram-based
optimization of cardiac
resynchronization therapy
Previous studies have linked QRS shortening to clinical response and
echocardiographic improvement.16,17 Therefore, shortening the
paced QRS duration with ECG-guided optimization could be a simple
and accessible method. Few studies have targeted QRS narrowing as
a goal and we are going to discuss it in this review. Lecoq et al.16
guided LV and right ventricular (RV) lead placement by QRS duration,
showing that the only independent predictor of response after a 6-
month follow-up was the amount of QRS shortening with BV pacing.
Arbelo et al.18 described the FOI method, which uses fusion with in-
trinsic conduction to achieve the shortest possible QRS, and showed
M. Pujol-López et al.
that FOI optimization resulted in further improvement of dP/dt. Most
recently, Jastrzebski et al.19 presented a retrospective mortality study
that reinforces the importance of QRS shortening in CRT. They
reported that immediate shortening of QRS duration with initiation
of CRT in patients with left bundle branch block (LBBB) strongly pre-
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dicts favourable prognosis. The authors suggested that shortening of
QRS should be considered a desirable acute electrocardiographic
endpoint of CRT device implantation procedure. In contrast, patients
with non-LBBB morphologies do not benefit from QRS narrowing
and have unfavourable prognosis similar to that seen in LBBB patients
without QRS narrowing.19
Electrocardiogram patterns in cardiac
resynchronization therapy
Guidelines include two ECG parameters to measure ventricular dys-
synchrony: QRS duration and the presence of LBBB QRS morphol-
ogy. Left bundle branch block causes delayed electrical and
mechanical activation of the left ventricle, which in turns results in
AV, VV, and intraventricular dyssynchrony. Electrocardiogram during
CRT can provide important information on LV lead location, pres-
ence of scar at LV pacing site, and fusion of intrinsic activation of RV
pacing with LV pacing.20,21
QRS pattern during right ventricular
pacing
In clinical practice, the RV apex is most often used in CRT as the RV
pacing site. Pacing the septum does not provide better response.22
Right ventricular pacing results in a LBBB-like QRS pattern in the pre-
cordial leads, with a negative QRS complex in lead V1 (Figure 1A).
However, a small early r-wave may occur in lead V1 during uncompli-
cated RV apical or outflow tract pacing. There is no evidence that this
small r-wave represents a conduction abnormality at the RV pacing
site.23 In general, QRS duration is usually more prolonged in RV pac-
ing when compared with LBBB.20 Right ventricular activation itself is
prolonged in RV pacing, when compared with intrinsic activation by
the His-purkinje system in LBBB. The area of latest activation is lo-
cated more basally in the lateral wall when compared with LBBB.24
QRS pattern during left ventricular
pacing
In CRT, the targeted pacing site is the LV lateral wall that is reached
via the coronary venous system. Left ventricular pacing typically
results in a right bundle branch block QRS pattern with a dominant
R-wave in V1 and negative QRS in lead I (Figure 1B). However, LV
pacing does not necessarily result in a negative QRS in lead I (espe-
cially in dilated and leftward displaced hearts with activation from
base to apex). A relatively narrow QRS complex during LV pacing is
associated with a better response to CRT.25
It is important to analyse pacing latency (interval from the pace-
maker stimulus to the onset of the earliest paced QRS complex) dur-
ing LV pacing. The impulse must travel from the epicardium to the
endocardium and often times in and around scar. Prolonged LV pac-
ing latency during simultaneous BV pacing can produce an ECG pat-
tern dominated by RV pacing, resulting in inadequate CRT.26
Electrocardiographic optimization techniques in CRT Page 3 of 11

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Figure 1 QRS pattern according to the stimulated site. (A) RV pacing results in a left bundle branch block-like QRS pattern in the precordial leads,
with a negative QRS complex in lead V1. (B) LV pacing results in right bundle branch block QRS pattern with a dominant R-wave in V1 and negative
QRS in lead I. (C) During biventricular pacing, the QRS morphology has recognizable features of the patterns produced by three wave fronts (RV pac-
ing, LV pacing, and intrinsic conduction). LV pacing, left ventricular pacing; RV pacing, right ventricular pacing.

QRS pattern during biventricular pacing
Biventricular pacing typically results in a merging of three wave fronts
of activation: RV, LV pacing, and intrinsic conduction. It results in a
conformational change in the QRS complex, generating a hybrid
morphology with recognizable features of the patterns produced by
each wave front. The QRS fusion contour is intermediate in shape
and duration between the QRS contours of the independent wave
fronts (Figure 1C).27
During BV pacing, the QRS axis is most often directed towards the
right superior quadrant, which results in a dominant R-wave in lead
aVR; however, a QRS axis in the other quadrants does not necessar-
ily indicate inappropriate programming or lead position. The QRS
complex during BV pacing most often has a dominant R-wave in lead
V1–V2, suggestive of contribution from LV pacing.
Sweeney et al.28 described that increasing R amplitudes in V1
through V2, indicating ventricular fusion, were associated with in-
creased probability of reverse remodelling. More recently, they per-
formed an extensive QRS analysis of the BV paced QRS morphology
in V1–V2 and reported the following predictors of reverse
remodelling27:
• Two BV fusion patterns in leads V1 and V2: QRS normalization or
a new or an increased R wave.
• QRS difference <_25 ms. Remodelling probability increases as
QRS difference takes on larger negative values. (QRS difference =
BV paced QRS  LBBB QRS duration, in ms).
Difference in haemodynamic response
in left ventricular vs. right ventricular
pre-excitation in cardiac
resynchronization therapy
There is a clear difference in haemodynamic response in LV vs. RV
pre-excitation in CRT. Left ventricular pacing alone may offer theo-
retical advantages over conventional BV pacing, potentially averting
deleterious effects from RV pacing. Verbeek et al.29 showed that LV
pre-excitation results in a haemodynamic response that is similar to
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Figure 2 Optimization of the interventricular delay using QRS width. Example of QRS width measurements showing 12-lead surface ECG;
measurements must be made during biventricular pacing in different VV intervals (LV pre-excited VV <0 ms; simultaneous biventricular VV = 0 ms;
RV pre-excited VV >0 ms). Width should be measured from the beginning of the QRS upstroke and not from the pacing spike. According to
this method, the VV that yielded the narrowest QRS was considered optimal.33 ECG, electrocardiogram; LV, left ventricle; RV, right ventricle; VV,
interventricular pacing delay.

BV pacing; their explanation is that the benefit of LV pacing primarily
originates from fusion of the LV pacing-derived wave front with that
of intrinsic conduction. The GREATER EARTH trial30 has shown that
non-responders to BV pacing may respond favourably to LV pacing,
suggesting a potential role as tiered therapy.
Along the same lines, Lumens et al.31 reported that both LV and
BV pacing improve systolic function of the dyssynchronous failing
heart, to a similar extent, in experimental animals and in patients.
They showed for the first time that the RV myocardium contributes
significantly to the improvement of LV pump function in pacing thera-
pies, especially LV pacing. During CRT, RV myocardium contributes
to LV pump function and this contribution differs between LV pacing
and BV pacing. This may explain why some patients respond better
to LV pacing and others to BV pacing, as demonstrated in the
GREATER EARTH study.
Optimization of the interventricular
delay using QRS width
The QRS width may be used as a surrogate endpoint for LV activa-
tion time. However, pacing from the left epicardium adds a latency
time of 30–40 ms, the time required for the pacing front to reach the
endocardium and fast conducting Purkinje fibres, as demonstrated by
pacing from the endocardium and epicardium at the same spot.32
The implication of that observation is that the QRS width should be
measured from the beginning of the QRS upstroke and not from the
pacing spike as previously shown.33 In the initial work by Vidal et al.,34
only VV interval was optimized, based on the shortest QRS, and a
fixed AV interval was programmed (Figure 2).
Vidal et al.34 found that optimizing CRT devices with interventricu-
lar activation delay measurement showed a good correlation with
the results obtained via echo-guided optimization in patients with
LBBB. Another relevant finding of this study was that the optimal VV
interval involved in most patients was LV preactivation. This observa-
tion is in agreement with the fact that most patients had a LBBB,
therefore, the latest activation was located at the left lateral wall, plus
the 30 ms compensation because of the pacing from the epicardium.
Perego et al.35 and van Gelder et al.36 obtained, respectively, 75% and
83% of LV preactivations as the optimal VV interval.
Tamborero et al.33 found that optimization of the VV interval by
measuring the QRS width from the earliest deflection obtained a bet-
ter acute haemodynamic response than the other VV optimization
methods. Measuring the QRS width from the earliest fast deflection
was the only method that significantly improved upon the haemody-
namic response obtained by programming a predefined VV of 0 ms in
all patients (LV dP/dt 925 6 178 vs. 906 6 183 mmHg/s; P = 0.003).
They observed that QRS narrowing was the best marker of improved
acute haemodynamic response to BV pacing. This explains previous
Electrocardiographic optimization techniques in CRT
findings of a relationship between the QRS narrowing induced by
CRT and a positive clinical response.37
Electrocardiographic vs.
echocardiographic optimization of the
interventricular pacing delay
Echocardiography-based methods to optimize the VV delay identify
the largest stroke volume or determine residual LV dyssynchrony
with TDI. These methods require expertise, are time-consuming and
are not routinely performed. Tamborero et al.38 compared the re-
sponse to CRT when VV optimization was randomly assigned to TDI
or QRS width criteria. At 6-month follow-up, they found a higher
percentage of echocardiographic responders, defined as neither
death nor heart transplantation and a LV end-systolic volume
(LVESV) reduction >10%, in the ECG optimized group (50% vs.
67.9%; P = 0.023). Interventricular optimization based on QRS width
obtained a higher percentage of responders in terms of LV reverse
remodelling compared with the TDI method. Applying the ECG cri-
teria instead of the TDI optimization method obtained an odds ratio
(OR) of 2.12 [95% confidence interval (CI) 1.106–4.063] for 6-month
echocardiographic response. The main finding of their study was that
selecting the VV value leading to the narrowest QRS, as measured
from the initial deflection, increased the probability of LV reverse
remodelling after CRT at mid-term follow-up, when compared with
TDI-based optimization. The limitation of these studies was that the
AV interval was fixed and did not take into account the role of fusion
with intrinsic conduction.
Methods of electrocardiographic
optimization
We will examine four methods of electrocardiographic optimization:
12-lead ECG; FOI; intracardiac electrogram-based algorithms; and
electrocardiographic imaging.
Twelve-lead electrocardiogram
The 12-lead ECG can be used in CRT for optimization of the pro-
grammed AV delay and VV interval by evaluating the morphology,
rather than QRS duration, of the BV-paced QRS complex.39 The
best AV delay and VV interval programming requires knowing the on-
set of intrinsic BV activation. Vernooy et al.40 described a method
that individually determines the onset of intrinsic ventricular activa-
tion. Stepwise increase of the AV delay during simultaneous BV pac-
ing starting with a short AV delay allows identification of the onset as
the AV delay where the QRS morphology changes. To ensure 100%
capture of LV pacing, the AV delay in CRT should preferably be pro-
grammed to a value shorter than the onset of intrinsic ventricular ac-
tivation, since exercise speeds up intrinsic AV conduction time.
An extensive echocardiographic study comparing mitral inflow
patterns with several programmed AV delays showed that echocar-
diographic optimal AV delays can be approximated using a simple
method of providing 30–40 ms separation between the end of the
P-wave and the ventricular pacing pulse in CRT.41
In relation to 12-lead ECG optimization of the VV interval,
Sweeney et al.28 reported that an increase in R-wave amplitude in V1
Page 5 of 11
and V2 is the best predictor of LV remodelling. Therefore, program-
ming of the VV interval should be used to create a QRS complex
with adequate contribution from LV pacing to maintain a dominant R
(R, Rs, or RS pattern) in leads V1–V2.39 Leads V1–V3 are especially
useful to identify the contribution from LV pacing and show the grad-
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ual change of the QRS complex with changing VV intervals.
van Deursen et al.42 showed (in canine LBBB hearts) that the QRS
vector reflects electrical dyssynchrony and that both the QRS vector
amplitude halfway between RV and LV pacing and the minimal QRS
vector area reflect optimal resynchronization and timing of stimula-
tion intervals in CRT. They propose a QRS morphology in leads V1–
V3 that resembles a value halfway between RV and LV pacing.
Considering all these findings, it is evident that the 12-lead ECG
could be used to easily optimize the programmed AV delay and VV
interval.
Fusion-optimized intervals optimization
method
Fusion with intrinsic conduction often obtains a shorter QRS due to
the addition of three wave fronts.43 In this context, Arbelo et al.18 de-
scribed the FOI method of optimizing CRT based on QRS duration,
which uses fusion with intrinsic conduction and avoids echocardio-
graphic AV and VV optimization.
From 2009 to 2011, 76 consecutive patients who were implanted
with a CRT device according to guidelines-based criteria and had a
LBBB were prospectively included. Patients with atrial fibrillation or
with AV conduction disturbances (AV interval >_250 ms or complete
AV block) were excluded. After CRT implantation, QRS measure-
ments (screen velocity 300 mm/s) were performed in three different
configurations: during spontaneous sinus rhythm, using the nominal
device programming, and after optimization of the AV and VV
intervals.
The FOI method is as follows:
a. First, to find the ‘fusion band’: during atrial sensing the AV interval is
progressively shortened with LV pacing only, starting with the longest
AV interval that allowed capture, and followed by decrements of
20 ms until the AV interval produces only LV capture. The AV interval
that provided the narrowest QRS is selected and considered as the
fusion-optimized AV interval (Figure 3). The QRS onset is considered
to be the start of the fast deflection and not the spike, as previously
reported.33
b. This procedure was repeated during atrial pacing at 10 b.p.m. above
the spontaneous sinus rhythm.
c. The VV interval is adjusted during atrial sensing, comparing QRS dura-
tion in different configurations (Figure 4): simultaneous RV and LV
pacing (VV = 0 ms), LV pre-excitation of 30 ms (LV30, also called
VV30), and RV pre-excitation of 30 ms (RV30, also called
VVþ30). The VV value that obtains the narrowest QRS is considered
the fusion-optimized VV interval.
These VV intervals (VV0, VV30, VVþ30) were chosen because
previous studies reported that most patients had the best VV value
within this range. Shorter or longer VV intervals may induce loss of
fusion (Table 1).
Screen speed of 300 mm/s may not be widely available except in
electrophysiology laboratories, but QRS measurements showed a
good correlation with the measurements at 50 mm/s.
Page 6 of 11
Figure 3 Description of fusion-optimized AV interval method. The AV interval that provided the narrowest QRS is selected and considered as the
fusion-optimized AV interval. The 12 leads of the surface ECG are recorded simultaneously and displayed in vertical alignment on the screen.18 AV,
atrioventricular; ECG, electrocardiogram; LV, left ventricle.
Mechanism of fusion-optimized intervals:
pacing with fusion
Fusion with intrinsic rhythm during pacing is considered when LV ac-
tivation is produced at least partially by intrinsic depolarization.43
Spontaneous activation over the right bundle provides a faster and
more organized RV contraction—sometimes the left bundle is not
completely blocked—and part of the LV can be activated from the in-
trinsic conduction. Fusion pacing creates three activation fronts, com-
pared with two during pure BV pacing (Figure 5), which nominal
device programming does not take into account.18,44
Several studies have pointed out the potential benefit of fusion
with the intrinsic rhythm. Vatasescu et al.43 used electroanatomic
mapping in 15 patients with CRT optimized by echocardiogram; BV
pacing (from the RV apex and LV) showed fusion with spontaneous
depolarization in eight patients, producing a higher 6-month response
rate and a more significant LVESV reduction. In patients with normal
AV conduction, CRT with fusion is superior to any optimized BV
configuration in improving LV as well as RV systolic performance.45,46
Cardiac resynchronization therapy optimization with FOI method
creates three activation wave fronts (instead of two during pure BV
pacing) shortening LV activation time (Figure 5).43
Benefits of fusion-optimized intervals
Arbelo et al.18 described the method and the benefits of FOI optimi-
zation. Baseline QRS was shortened more by FOI (59 6 19 ms) than
M. Pujol-López et al.
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by nominal settings (40 6 21 ms; P < 0.001). Moreover, using FOI,
86% of the patients achieved >10% shortening of the QRS, and none
had prolonged QRS duration, compared with results using the nomi-
nal values. In addition, the FOI method is faster (the duration of the
optimization of the AV and VV interval was 15.5 6 7.3 min) than
echocardiography optimization.
Regarding the invasive haemodynamic evaluation,18 the QRS nar-
rowing was correlated with an increase in LV dP/dtmax independently
of the baseline QRS duration. Baseline dP/dtmax improvement was
greater using FOI (127 6 95 mmHg/s) than in nominal settings
(102 6 71 mmHg/s; P = 0.05). On the other hand, FOI significantly re-
duced intraventricular LV dyssynchrony compared with baseline val-
ues, as assessed by TDI with the septal-to-lateral method and by
decreased presence of septal flash (78% vs. 42% of patients; P < 0.01).
Improvement of reverse remodelling by
using fusion-optimized intervals
Trucco et al.8 compared echocardiographic LV reverse remodelling
of CRT using FOI to nominal programming in a randomized study of
180 consecutive CRT patients. Left ventricular remodelling was de-
fined as >15% decrease in LVESV at 12-month follow-up. At
12 months, LV reverse remodelling was achieved in a larger propor-
tion of the FOI group [74% vs. 53%, respectively (OR 2.02, 95% CI
1.08–3.76); P = 0.026]. There was a correlation (r = 0.23; P = 0.01) be-
tween response and the degree of QRS narrowing: patients with the
Electrocardiographic optimization techniques in CRT
Figure 4 Description of fusion-optimized VV interval method.
Once the fusion-optimized AV interval is selected, the optimal VV
interval is adjusted during atrial sensing. The optimal VV interval is
then chosen by comparing the QRS duration in LV pre-excited, si-
multaneous biventricular, or RV pre-excited configuration.18 LV, left
ventricle; RV, right ventricle; VV, interventricular pacing delay.
most QRS narrowing experienced the greatest benefit, as measured
by echocardiographic remodelling. In addition, after 12 months of
CRT, fewer patients in the FOI group were classified as negative res-
ponders (11% vs. 24% in the nominal settings group; P = 0.041).
Although the small study by Trucco et al. did not find differences in
clinical endpoints, in a substudy of the MADIT CRT (Multicenter
Automatic Defibrillator Implantation With Cardiac Resynchronization
Therapy) trial by Solomon et al.,47 LV remodelling predicted a lower
risk of heart failure or death. Multivariable analysis identified reverse
LV remodelling as the best predictor of long-term survival in a study
by Yu et al.48
In conclusion, electrocardiographic optimization of the AV and VV
intervals to achieve fusion with intrinsic conduction significantly re-
duced QRS duration and increased LV remodelling, compared with
default programming of CRT devices, at 12-month follow-up.
Advantages and limitations of fusion-
optimized intervals optimization
The goal of FOI optimization is QRS narrowing, benefitting from fu-
sion with intrinsic conduction. It has shown haemodynamic improve-
ment (increase in LV dP/dt), reduction of dyssynchrony, and increase
of LV remodelling.8 Moreover, QRS shortening with BV stimulation
has shown positive clinical response to CRT.16 In addition, CRT with
fusion is superior to any optimized BV configuration in improving LV
as well as RV systolic performance.45,46
Very recent data published by Jastrzebski et al.19 shows a strong re-
lationship between mortality risk and shortening of the QRS, albeit
only in patients with LBBB. Thus, shortening of QRS duration predicts
favourable prognosis in patients with LBBB.
The FOI method is feasible, fast, can be performed during implant,
and avoids complex measurements (echocardiography or invasive
Page 7 of 11
Table 1 Best VV fusion-optimized QRS configurations
to obtain the narrowest QRS
Fusion-optimized QRS Arbelo et al.18
configurations % of patients
.................................................................................................
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Simultaneous biventricular pacing 37
LV pre-excitation (VV30) 29
RV pre-excitation (VVþ30) 8
LV pacing alone 26
LV, left ventricle; RV, right ventricle; VV, interventricular pacing delay.
haemodynamic techniques) for optimization. Therefore, it can be
used in clinical practice and allows better response to CRT.
However, FOI may have limitations. The main potential limitation
of the FOI method is that it must be reprogrammed if there is a
change in AV conduction. This may lead to pseudo-fusion or a change
in the best interval due to variations in intrinsic AV time.8
Furthermore, its behaviour during exercise has not been analysed. At
this point, it could play an important role to incorporate FOI as an au-
tomatic algorithm—similarly to how SyncAV algorithm49 (St Jude
Medical—Abbott) automatically adjusts the AV interval—to get a
narrower QRS.
Studies performed have excluded patients with complete AV
block, AV prolongation, or atrial fibrillation. Fusion-optimized inter-
vals is suitable for those in sinus rhythm with LBBB and normal AV
conduction. Although FOI may be useful in patients with AV block,
atrial fibrillation, or prolonged AV, these patients cannot benefit from
intrinsic conduction.8 We need studies to determine if it could work
and have value in these cases—in which fusion would not play a role.
Fusion-optimized intervals optimization may be valuable in patients
with non-LBBB (with wide QRS) but further research is needed in
this field.
Some factors to take into account that influence the response to
TRC and may affect FOI optimization are gender, scar tissue, QRS
duration, and PR interval.
Women are more likely to benefit from CRT than men.50 They
have more non-ischaemic aetiology and LBBB morphology, both as-
sociated with better CRT outcomes, compared with men. Moreover,
women with dilated cardiomyopathy usually have less myocardial
scar than their male counterparts.51 More directly related to CRT
programming, gender differences in ECG parameters include shorter
PR interval and short QRS duration in women.52 Further studies are
needed to describe the influence of a shorter PR in women in the AV
optimization of TRC devices.
Cardiac resynchronization therapy has proven to be more effec-
tive in reducing adverse clinical events in those patients with a QRS
duration greater than 150 ms.53 Left ventricular reverse remodelling
and clinical responses increase progressively with increasing baseline
QRS duration, but mainly in those patients with LBBB morphology.54
Finally, the extent of myocardial scar tissue may be one of the key
determinants of poor response in patients with CRT.
Electrocardiogram optimization could help in this context because
wide and fractionated LV-paced QRS complexes may indicate pacing
in scar tissue.39
Page 8 of 11
Figure 5 Ventricular depolarization and ECG morphology. Comparison of the pattern of ventricular depolarization and ECG morphology in pure
biventricular pacing (left panel) and fusion biventricular pacing (right panel).44 ECG, electrocardiogram.
Intracardiac electrogram-based
algorithms
QRS shortening is not maximal with nominal programming, but it
could be facilitated by automatic device-based algorithms in order to
accommodate variability in intrinsic intervals. As we have mentioned,
few studies have targeted QRS narrowing as a goal in optimization. In
the case of automatic algorithms, Varma et al.49 used a device-based
algorithm (SyncAV, St Jude Medical—Abbott) that automatically
adjusts paced AV delay according to intrinsic AV conduction. They
compared different pacing configurations: nominal simultaneous BV,
BV þ SyncAV, and LV-only pacing þ SyncAV. BV þ SyncAV with the off-
set value individualized to minimize QRS duration yielded the short-
est overall QRS duration and was the only configuration without
QRS prolongation in any patient.
There are other intracardiac electrogram-based algorithms:
AdaptivCRT, Medtronic; QuickOpt, St Jude Medical—Abbott;
SmartDelay, Boston Scientific. Nevertheless, these algorithms do not
verify if the narrowest QRS has been obtained. The FOI method, al-
though it requires manual measurements, is directly focused on
obtaining the narrowest QRS.
AdaptivCRT (Medtronic) algorithm adapts the sensed and paced AV
intervals each minute to accommodate natural variations in intrinsic
AV over time. The VV offset is then determined based on the intrinsic
AV delay and interval from the sensed RV electrogram to the end of
the QRS complex.55 The algorithm uses intrinsic intervals to provide
RV-synchronized LV pacing when AV conduction is normal (fusion
with the intrinsic activation), or BV pacing otherwise. It has shown sig-
nificant increase in effective LV pacing over echo-optimized CRT56
and better clinical outcomes in a secondary analysis of the adaptive
M. Pujol-López et al.
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CRT trial.9 This fusion algorithm of Medtronic seems to be promising,
but more studies are needed.
QuickOpt (St Jude Medical—Abbott) calculates the optimal AV de-
lay and VV offset based on intracardiac electrograms measured from
the right atrium, RV, and LV leads. It determines the optimal AV and
VV delays that achieve the best electromechanical resynchronization
of LV myocardial segments. The VV delay is estimated using the for-
mula VV = 0.5  (D þ e) (where the conduction delay D is the differ-
ence between the time of peak intrinsic activation at the LV vs. the
RV lead; and e is the difference in VV conduction delay between two
ventricular-paced propagated waveforms).57 Validation studies have
shown conflicting results.
SmartDelay (Boston Scientific) electrogram-based method calcu-
lates sensed and paced AV delays that provide maximum haemody-
namic response by accounting for three inputs: intrinsic AV intervals,
interventricular timing, and LV lead location.58 Ellenbogen et al.12
showed that optimization with the SmartDelay algorithm was not dif-
ferent from echocardiographically determined AV interval optimiza-
tion or a fixed AV delay of 120 ms.
Electrocardiographic imaging
As previously commented, QRS shortening is related to clinical re-
sponse and echocardiographic improvement. However, this parame-
ter is not necessarily related to a good activation sequence. Body
surface activation mapping59 is a non-invasive technology based on a
vest (or belt) with multiple body surface electrodes (Figure 6). Body
surface activation mapping simultaneously records ECG activity and
allows obtaining an electrocardiographic image of ventricular activa-
tion. The vest measures body-surface unipolar ECGs and generates
Electrocardiographic optimization techniques in CRT
Figure 6 Body surface activation mapping (BSAM). BSAM is a
technology for generating activation maps based on a vest with mul-
tiple electrodes (this model uses 64 electrodes). It simultaneously
records ECG activity and allows obtaining an electrocardiographic
image of ventricular activation. Image provided by Andreu Martı́nez
Climent.
activation maps using using multiple electrodes placed on the thorax
(anterior and posterior electrodes).60 Isochronal maps of electrical
activation are created based on body surface activation time at each
electrode. Software calculates the standard deviation of the individual
activation times as a measure of electrical dyssynchrony.
Evaluation of the ECG Belt System is in process [ECG BELT
FOR CRT RESPONSE STUDY ClinicalTrials.gov identifier:
NCT03504020; Optimization of Multipoint Pacing through Fusion
Optimized Intervals (FOI) and Electrocardiographic Imaging (ECGI)
in Cardiac Resynchronization Therapy in our centre].
Electrocardiographic Imaging61 with ECG vest/belt is a promising
tool that could advance CRT optimization and patient selection,
pending the results of the ongoing studies.
Future perspectives in
optimization techniques
During the last years, multipoint stimulation has been developed: a
LV lead with four different pacing electrodes and a device with multi-
ple pacing options. Multipoint stimulation allows capture of a larger
region of LV myocardium by pacing from widely spaced electrodes.
Zanon et al.62 showed that multipoint pacing elicited significantly
greater QRS narrowing than conventional BV pacing at any site.
Multipoint pacing is also associated with a decrease in endocardial ac-
tivation time evidenced with invasive electroanatomic mapping of the
left ventricle.63 Since multipoint pacing may be superior to traditional
BV pacing, it may be important to optimize the timing in multipoint.
Page 9 of 11
In this context, FOI could be combined with multipoint stimulation
to try to shorten the QRS; however, more research is needed.
Since dynamic device-based algorithms may facilitate narrowing of
the QRS—adjusting the intrinsic AV interval variability and the VV
delay when necessary—we also need a head-to-head comparison
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with FOI optimization in future studies. Moreover, as the main limita-
tion of FOI is that it should be reprogrammed if there is a change in
AV conduction, this opens the way to an automatic algorithm based
on FOI.
A recent study by Huntjens et al.,64 with computer simulations,
revealed that intrinsic interventricular dyssynchrony is the dominant
component of the electrical substrate driving the response to CRT—
and intrinsic intraventricular dyssynchrony would play a minor role in
this respect. More studies, in this direction, with automatic algorithms
and with FOI to find out which mechanism is the predominant will be
necessary.
Head-to-head comparison of all CRT optimization methods is nec-
essary to establish which is most effective in which particular
situation.
Review methodology
Comprehensive review with the aim to summarize research in the
field of ECG optimization techniques in CRT. The main database
used was PUBMED/MEDLINE with the following keywords (filters:
humans and adults):
• Electrocardiographic optimization AND resynchronization
therapy.
• Electrocardiogram optimization techniques AND resynchroniza-
tion therapy.
• Electrocardiographic AND optimization AND resynchronization.
• Optimization AND resynchronization AND algorithms.
Bibliographies of those papers that match the eligibility criteria
were searched by hand to identify any further, relevant references.
With the different searches, 173 articles were initially selected, of
which 64 were applicable, relevant and finally were cited for the
review.
Acknowledgements
The authors thank Elaine Lilly, for manuscript editing, and Neus
Portella, for administrative and editing support.
Conflict of interest: none declared.
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