Hemodynamic comparison of different multisites and multipoint pacing strategies in cardiac resynchronization therapies
Journal of Interventional Cardiac Electrophysiology
Hemodynamic comparison of different multisites and multipoint pacing strategies in cardiac resynchronization therapies
Francesco Zanon 0 1 2 4 5 6
Lina Marcantoni 0 1 2 4 5 6
Enrico Baracca 0 1 2 4 5 6
Gianni Pastore 0 1 2 4 5 6
Giuseppina Giau 0 1 2 4 5 6
Gianluca Rigatelli 0 1 2 4 5 6
Daniela Lanza 0 1 2 4 5 6
Claudio Picariello 0 1 2 4 5 6
Silvio Aggio 0 1 2 4 5 6
Sara Giatti 0 1 2 4 5 6
Marco Zuin 0 1 2 4 5 6
Loris Roncon 0 1 2 4 5 6
Domenico Pacetta 0 1 2 4 5 6
Franco Noventa 0 1 2 4 5 6
Frits W. Prinzen 0 1 2 4 5 6
0 Interventional Cardiology Unit, Santa Maria Della Misericordia General Hospital , Rovigo , Italy
1 Cardiology Department, Santa Maria Della Misericordia General Hospital , 140, Viale Tre Martiri, 45100 Rovigo , Italy
2 Arrhythmia and Electrophysiology Unit, Santa Maria Della Misericordia General Hospital , Rovigo , Italy
3 Francesco Zanon
4 Cardiovascular Research Institute Maastricht (CARIM) , Maastricht , The Netherlands
5 Department of Molecular Medicine, University of Padua , Padua , Italy
6 St. Jude Medical , Agrate Brianza , Italy
Purpose In order to increase the responder rate to CRT, stimulation of the left ventricular (LV) from multiple sites has been suggested as a promising alternative to standard biventricular pacing (BIV). The aim of the study was to compare, in a group of candidates for CRT, the effects of different pacing configurations-BIV, triple ventricular (TRIV) by means of two LV leads, multipoint (MPP), and multipoint plus a second LV lead (MPP + TRIV) pacing-on both hemodynamics and QRS duration. Methods Fifteen patients (13 male) with permanent AF (mean age 76 ± 7 years; left ventricular ejection fraction 33 ± 7%; 7 with ischemic cardiomyopathy; mean QRS duration 178 ± 25 ms) were selected as candidates for CRT. Two LV leads were positioned in two different branches of the coronary sinus. Acute hemodynamic response was evaluated by means of a RADI pressure wire as the variation in LVdp/dtmax. Results Per patient, 2.7 ± 0.7 veins and 5.2 ± 1.9 pacing sites were evaluated. From baseline values of 998 ± 186 mmHg/s, BIV, TRIV, MPP, and MPP-TRIV pacing increased LVdp/dtmax to 1200 ± 281 mmHg/s, 1226 ± 284 mmHg/s, 1274 ± 303 mmHg, and 1289 ± 298 mmHg, respectively (p < 0.001). Bonferroni post-hoc analysis showed significantly higher values during all pacing configurations in comparison with the baseline; moreover, higher values were recorded during MPP and MPP + TRIV than at the baseline or during BIV and also during MPP + TRIV than during TRIV. Mean QRS width decreased from 178 ± 25 ms at the baseline to 171 ± 21, 167 ± 20, 168 ± 20, and 164 ± 15 ms, during BIV, TRIV, MPP, and MPP-TRIV, respectively (p < 0.001). Conclusions In patients with AF, the acute response to CRT improves as the size of the early activated LV region increases.
Heart failure; Multisite pacing; Multipoint pacing; Dual LV site pacing; Hemodynamic optimization; Electrical delay
A selected group of patients with systolic heart failure (HF)
a n d p r o l o n g e d Q R S m a y b e n e f i t f r o m C a r d i a c
Resynchronization Therapy (CRT) [
]. However, one third
of patients referred for this therapy do not show a favorable
long-term outcome . One of the reasons for the lack of
response is the suboptimal position of the left ventricular
(LV) pacing lead [
]. As described in our previous paper [
we usually target the most electrically delayed site in order to
achieve the optimal resynchronization. Novel techniques
suggested by some authors are based on the concept that
stimulating a larger area of the LV may improve the success rate of
CRT. Multisite LV pacing can be carried out with several LV
leads in separate coronary sinus (CS) veins [
] or by means
of a single multipolar lead capable of delivering multiple
stimuli within one CS vein [
]. Our study aimed to
compare the acute effects of four pacing configurations in a
selected group of patients in permanent atrial fibrillation (AF):
biventricular (BIV), multiple site pacing by means of two
LV leads (triple ventricular, TRIV), multipoint pacing (MPP)
through a single quadripolar lead, and the combination of
TRIV and MPP.
Fifteen consecutive patients with permanent AF and
indications for the implantation of a CRT-device, in accordance with
the European Society of Cardiology/European Heart Rhythm
Association (ESC/EHRA) guidelines [
], were enrolled in a
In our center, the dual LV site technique is part of common
practice in AF patients who are candidates for CRT. We
usually optimize the best pacing site during the CRT implantation
procedure by means of Q-LV and hemodynamic
measurements. The implanting method was described in our previous
]. Briefly, the right ventricular (RV) lead was
implanted in the mid-septum, according to our standard
implantation procedure. Cannulation of the CS and
subcannulation of all suitable collateral veins were performed
by means of a telescopic approach.
Pacing sites were classified as anterior, antero-lateral,
lateral, postero-lateral, and posterior segments (in the left
anterior oblique view) and as basal, mid, and apical ventricular
segments (in the right anterior oblique view), in accordance
with the scheme established by Singh et al. [
Suitable pacing sites were systematically screened by
measuring the local electrical delay (Q-LV) during intrinsic
activation of the LV, by means of a BARD Labsystem Pro EP
V2.4a (C.R. Bard Inc., Lowell, MA), and the LVdp/dtmax by
means of a Certus Pressure Wire and PhysioMon software (St.
Jude Medical Systems AB, Uppsala, Sweden) during all
pacing configurations and during intrinsic rhythm. LVdP/dtmax
at baseline and during the different pacing protocols was
calculated over an interval of 15 s; premature ventricular
contractions were eliminated electronically. A period of 30 s was
allowed to elapse after any change in pacing settings or lead
position to allow hemodynamic stabilization. To minimize the
impact of respiration and physiological variation, each 15-s
LVdP/dtmax value was measured during three separate
recordings for each test configuration [
In accordance with the guidelines, before CRT
implantation, all patients underwent optimization of medical therapy,
which included the up-titration of beta-blocker treatment. At
the time of implantation, the mean heart rate of the whole
population was 59 ± 7 (range 52–71 bpm). With the intention
to obtain 100% of ventricular capture, the pacing protocol was
set to 10 beats above the basal heart rate (mean pacing rate was
70 ± 4, range 65–80). Twelve-lead QRS morphology was
examined beat by beat in the EP system in every pacing setting
by an expert electrophysiologist to confirm continuous
capture and avoid fusion beats. The first step was to place the
quadripolar lead (Quartet™ 1458Q, St. Jude Medical) in
every single vein available for cannulation. As per protocol, in
every vein we collected data on the Q-LV interval measured
from the proximal dipole, defined as LV1 (electrodes M3-P4,
inter-dipole length 17 mm), and from the distal dipole, defined
as LV2 (electrodes D1-M2 inter-dipole length 20 mm); we
also assessed the hemodynamic effect by measuring the
LVdp/dtmax at every site. A second bipolar lead, defined as
LV3 (Quickflex MicroTM 1258T, St. Jude Medical), was then
implanted, usually in an anterior CS vein, and all the
measurements were repeated in order to obtain all the possible
combinations of pacing between the two leads. We started with BIV
pacing with the proximal or distal dipole of the quadripolar
lead (RV + LV1 or RV +LV2, depending on the best Q-LV),
then TRIV (RV + LV1 + LV3 or RV + LV2 + LV3, depending
on the best Q-LV), then MPP (RV + LV1 + LV2) and finally
TRIV plus MPP (RV + LV1 + LV2 + LV3) in every vein (an
explanatory example of all the data collected is displayed in
Fig. 1). To explain our procedure more clearly, if patients had
only two available veins, the quadripolar lead was implanted
in the one with the longest Q-LV; if 3 or more veins were
available, the quadripolar lead was tested in all veins,
including those with non-optimal Q-LV. We did not collect data on
veins that were visualized but not cannulated. MPP
stimulation was performed by means of simultaneous pacing from the
two dipoles of the quadripolar lead.
The sequence of site testing was not randomized in order to
reduce as much as possible the procedural time.
The definitive position of the quadripolar lead was the
optimal pacing site, defined as the most delayed site in
terms of Q-LV, while the second bipolar lead was
positioned in a different CS vein, usually in the most
anatomically remote vein from the quadripolar lead. We evaluated
the effect of the different pacing configurations on
hemodynamics and QRS duration, as schematically illustrated in
Table 1 and Fig. 2.
In all configurations, pacing was performed by means of a
triple-chamber pacing system analyzer (Merlin EX3100 PSA,
St. Jude Medical). TRIV was obtained by connecting the
bipolar LV lead to the atrial channel of the PSA, and by
programming the atrio-ventricular delay to the minimum
available value of 25 ms. The RV-LV delay was always set at 0 ms.
During MPP, the LV1 and LV2 of the quadripolar lead were
paced simultaneously from the LVoutput of the pacing system
analyzer by means of a custom-made epsilon-shaped adapter.
TRIV+MPP was obtained by combining the previous
The two LV leads were implanted definitively, as per
protocol in our center. The bipolar LV lead was connected to the
atrial port of the device and programmed with the shortest
available AV delay (25 ms).
2.1 Statistical analysis
Our aim was to evaluate the improvement in ventricular
function, as estimated by the change in LV-dP/dtmax and
QRSwidth from the basal measurement, obtained by switching the
cardiac pacing protocol from single-site BIV, TRIV, MPP to
antero-lateral vein. Q-LV measurements at each site are reported. c Final
lead positions in LAO view. d Effects on LVdp/dtmax and on QRS width
(e) during different pacing protocols. The values at the top of panels d and
e indicate the best measurements. The dots in the graphs represent all the
data collected for each pacing configuration. Abbreviations are in the text
MPP + TRIV pacing in the same subject in a one-arm
(intrapatient) study. The instrumental data collected were tabulated
along with topographic and protocol information and patients’
We used the Brepeated measures analysis of variance^ to
estimate variations in within-subject measurements of LVdp/
dtmax and QRS-width; the Greenhouse-Geisser adjustment
was applied to degrees of freedom, and equal weights were
attributed to measurements. The Bonferroni correction was
MPP + TRIV
BIV biventricular pacing (RV pacing plus LV pacing from one of the two dipoles of the quadripolar lead, LV1), TRIV tri-ventricular pacing (RV pacing
plus LV1 plus a second LV bipolar pacing lead, LV3), MPP multipoint pacing (RV pacing plus pacing from both dipoles of the quadripolar lead, LV1 and
LV2), MPP + TRIV tri-ventricular plus multipoint pacing (pacing from RV, LV1, LV2, and LV3)
LV pacing from one of the two dipoles of the quadripolar lead, LV1),
TRIV tri-ventricular pacing (RV pacing plus LV1 plus a second LV
bipolar pacing lead, LV3), MPP multipoint pacing (RV pacing plus pacing
from both dipoles of the quadripolar lead, LV1 and LV2), MPP + TRIV
tri-ventricular plus multipoint pacing (pacing from RV, LV1, LV2, and
used for pairwise planned comparisons between the pacing
The analyses were conducted on Ball measurements^
collected from patients (78 measurements).
ICM ischemic cardiomyopathy, NYHA New York Heart Association,
LVEF left ventricular ejection fraction, ESVi End Systolic Volume index,
LBBB left bundle branch block, RBBB right bundle branch block, IVCD
inter-ventricular conduction delay, PM DEP pacemaker dependent,
CRTP CRT-pacemaker, CRT-D CRT-defibrillator, NT-proBNP N-terminal pro
b-type natriuretic peptide, ACE-ARB ACE inhibitors (angiotensin
converting enzyme inhibitors) and ARB (angiotensin-receptor blockers)
Quad lead position means the area covered by the entire quadripolar complex. Total numbers of veins and explored sites in each patient are also displayed
p values for difference combinations related to gain in
LVdP/dtmax and QRS width during pacing protocols are
reported in Tables 5 and 6, respectively.
Our data indicate that, in CRT patients with AF, pacing from a
wider area in the LV acutely increases contractility more than
standard BIV does. Most importantly, MPP increases
contractility at least as much as TRIV, while it has the advantage of
requiring only one LV lead. Combining MPP + TRIV can
increase contractility even further, indicating that increasing
the area of early activation on the LV increases the
4.1 Increasing the early activated area in the LV
The present study showed a two-step increase in the acute
hemodynamic effect of CRT, beyond that due to conventional
BIV pacing: a first increase yielded by TRIV or MPP alone
and a further increase yielded by combining the two
approaches. Because each of the two approaches aims to
increase the size of the early activated region, these data support
the idea that increasing this region is beneficial for
resynchronization; this is also evidenced by a stepwise
reduction in QRS duration. Several studies support the idea that
QRS narrowing by CRT is a strong determinant of both
echocardiographic and clinical response to CRT [
While TRIV pacing can be considered to create an early
activated region with a largely circumferential orientation
Fig. 4 Gain in LVdp/dtmax
yielded by the different pacing
modes, during biventricular
(BIV), triple ventricular (TRIV),
multipoint (MPP), and MPP +
TRIV pacing protocols vs
baseline (considering all pacing
sites, 78 series of measurements
in the 15 patients)—Bonferroni
post-hoc analysis showed
significant differences from basal
in all pacing configurations;
significant differences were
observed between BIV and MPP,
between BIV and MPP + TRIV,
and between TRIV and MPP +
(between two contributory venous zones), MPP creates a more
baso-apically oriented zone. It is interesting that the orientation
of the early activated zone does not seem to matter, as both
approaches result in similar hemodynamic and
electrophysiological benefit in comparison with conventional BIV pacing.
Finally, the observation that the combination of TRIV
and MPP further improves CRT response is a further
argument in favor of the idea that increasing the early
activated region on the LV increases the effect of CRT. This
may raise the question of what the optimal size of this
early activated region may be. However, animal studies
indicate that the additional hemodynamic benefit of
pacing more than four sites may be small [
4.2 Multisite vs. multipoint pacing
The idea of pacing from multiple sites has already been
expounded upon by various authors [
6, 7, 19
], who used
two leads in two different veins of the CS tree (TRIV). This
technique has been demonstrated to be feasible and has
yielded promising results from a clinical point of view,
providing improvement in ejection fraction (EF) and ventricular
]. Other authors have demonstrated a favorable
effect of triple-site pacing on NYHA class in comparison with
standard dual-site pacing. In a study by Rogers et al. [
triple-site pacing was obtained by applying dual-site pacing
to either the right or left ventricle and proved significantly
Fig. 5 Effects on QRS width
during biventricular (BIV), triple
ventricular (TRIV) by means of
two LV leads, multipoint (MPP),
and multipoint plus second LV
lead (MPP-TRIV) pacing
protocols vs baseline (considering
all pacing sites, 78
post-hoc analysis showed
significant differences from the
baseline in all pacing
superior to bipolar pacing in terms of the 6-min walking test,
Minnesota living with HF score, ventricular remodeling, and
In a study by Behar [
], 19 patients were paced at two
different LV sites by means of two LV leads connected to a
bifurcating adapter. While this technique yielded beneficial
hemodynamic results on implantation, it also proved
problematic in patients in sinus rhythm. Indeed, the two LV leads need
to be connected to the device through an adapter and are
stimulated from one source, while they may have different
impedances. On the other hand, TRIV pacing in patients with
AF, as in the study by Leclercq [
] and in our study, is more
feasible because the second LV lead is connected to the atrial
port. However, this solution is limited by the minimum AV
interval, which is between 25 and 30 ms in the majority of
commercially available devices.
The introduction of quadripolar technology has enabled a
larger area to be paced from a single multipolar lead, and
initial experiences documented significant improvements in
] and mechanical dyssynchrony [
Our previous experience [
] extended the concept of the
benefit of MPP, in that acute hemodynamic improvement
was obtained in every single vein; indeed, on studying 29
patients with an average of 3.2 veins and 6.3 pacing sites per
patient, we observed an improvement in LVdp/dtmax at all
sites, including the best and worst positions, which suggests
that this pacing modality is widely applicable. Our acute
results were confirmed in a subsequent study in which MPP,
optimized on implantation as previously described, proved
significantly superior in terms of remodeling and clinical
status to conventional BIV without optimization [
also demonstrated the positive effects of MPP at 3-month and
1-year follow-up examinations [
]. Finally, a large
multicenter Italian experience confirmed the favorable effects of
MPP in comparison with standard BIV . Recently, the
IDE study met the pre-specified hypothesis of
noninferiority of MPP to standard BIV in terms of safety and
effectiveness. Moreover, among patients randomized to
MPP, those paced from anatomically distant poles displayed
a significantly higher rate of response than those paced from
close poles [
The question of whether acute improvement in LVdP/dtmax
predicts long-term clinical benefit needs more evidence.
However, our previous experience [
] indicates that, on
implantation, acute optimization by means of LVdp/dtmax and
electrical delay correlates positively with clinical and
remodeling improvement at one-year follow-up. Previously, Duckett
found that a 10% increase in LVdp/dtmax on pacing predicted
LV reverse remodeling at 6-month follow-up [
The present study provides the first head-to-head
comparison between the two modalities of pacing a larger area,
multisite (TRIV) and multipoint pacing (MPP). The finding that
MPP yields at least the same hemodynamic benefit as TRIV
pacing suggests that MPP may be preferred to TRIV pacing,
as the implantation technique of MPP technology is as simple
as that of a bipolar LV lead and avoids placement of a second
lead, with its accompanying increased risk of dislodgement.
This was an acute, single-center, non-randomized study; the
patient sample size was limited, and the pacing protocol
configurations were conditioned by the limitations of the
currently available technology. Moreover, as outlined in the methods
section, due to the long protocol procedure and in order to
reduce as much as possible the duration of the implant, we
did not randomize the pacing protocol series. As result, the
lack of a randomization of the protocol might have influenced
the hemodynamics by introducing linear effects. Furthermore,
the acute hemodynamic results may not lead to long-term
clinical benefit. The implications of this study should be
confirmed in a larger, randomized, prospective, multicenter,
Pacing from a wider area, as in TRIV and MPP, increases
electrophysiological and hemodynamic benefits in
comparison with standard BIV pacing, and a further improvement is
achieved by TRIV + MPP. This suggests that a larger early
activated region increases the efficacy of CRT. In accordance
with the concept that Bless is more,^ it appears that MPP,
which requires only one lead, is probably the most convenient
technique in terms of risk/benefit ratio.
Acknowledgments We thank Paola Raffagnato, Antonella Tiribello, and
Graziano Boaretto (S. Maria Della Misericordia Hospital, Rovigo, Italy)
for their technical support in collecting data.
Compliance with ethical standards
Conflict of interest Dr. Zanon has some conflicts of interests, having
received modest speaker fees from Boston Scientific, Medtronic, St. Jude
Medical, and Livanova. Dr. Prinzen receives research grants from
Medtronic, MSD, EBR Systems, and Proteus Biomedical. Domenico
Pacetta is an employee of St. Jude Medical Italy. The other authors report
Ethical approval The local ethics board approved the study.
Informed consent All patients provided written informed consent.
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