Study protocol
All included patients underwent implantation of a CRT device and were
tested for each of the 3 pacing configurations (MPP, SPP-FOI, MPP-FOI).
The study protocol is summarized in Figure 1 . Written consent
was obtained for each patient. The protocol was reviewed and approved by
the local institutional research ethics committee (HCB/2018/0388).
a) CRT device implantation
All patients underwent CRT device implantation according to routine
clinical practice. Each patient was implanted with a commercially
available MPP-capable CRT system that included a quadripolar LV lead and
a compatible CRT device. The indications for pacemakers or
defibrillators were based on comorbidities and clinical factors limiting
the quality of life or life expectancy. The atrial lead was positioned
in the right atrial appendage, and the right ventricular (RV) lead was
positioned in the RV apical septum. The LV quadripolar leads (four
electrodes: D1, M2, M3, and P4 from distal to proximal) preferentially
targeted a lateral or posterolateral branch of the coronary sinus.
Positions were defined using radiological criteria and checked in
30-degree right and left anterior oblique projections immediately after
implantation using fluoroscopy and the next day using X-ray.
b) Electrocardiographic optimization
Device optimization was performed immediately after implantation in the
operating room. The QRS duration was measured during intrinsic rhythm
and with the three specific configurations: MPP, SPP-FOI, and MPP-FOI.
The 12 leads of a surface electrocardiogram (ECG) were simultaneously
displayed in vertical alignment and digitally recorded for off-line
measurement (WorkMate Claris; St. Jude Medical, Abbott). Time
measurements were taken at a screen velocity of 200 mm/s by two
experienced observers, unaware of the configurations, using a digital
cursor with an accuracy of 1 ms; the mean across 3 consecutive cycles
was calculated and recorded. The onset of QRS was considered to be the
start of the fast deflection9 to avoid the average
45-ms transmural delay due to epicardial pacing of the LV lead. At
discharge, the device was programmed with the configuration that
provided the narrowest QRS duration.
Multipoint pacing programming: Multipoint pacing was programmed as
previously described.3,4,14 The MPP configuration was
chosen to first pace using the distal electrode (primarily D1,
secondarily M2) as the cathode (LV1) and then the proximal electrode
(primarily P4, secondarily M3) as the cathode (LV2). Two LV vectors with
wide interelectrode cathode spacing were selected as the final LV1/LV2
vectors, utilizing the following order of preference: D1/P4
> D1/M3 or M2/P4 (Figure S1 ). When the LV pacing
vector showed a capture threshold larger than 3.5 V and/or phrenic nerve
stimulation (PNS), it was excluded. Programming included the following
intervals: (1) fixed AV interval, 130 ms; (2) RV-LV2 (∆1) interval, 5
ms; and (3) LV1-LV2 (∆2) interval, 5 ms (∆1 and ∆2 with the minimal
programmable delay).
Fusion-optimized intervals method: FOI optimization was performed as
described elsewhere.7,10 Briefly, the fusion band was
determined with atrial sensing and ventricular pacing with the
anatomically furthest electrode in the LV lead. Pacing was initially
tested with the longest AV interval that allowed LV capture; the AV
interval was subsequently shortened in 20-ms decrements until LV-only
capture was achieved. The AV interval that yielded the narrowest QRS was
chosen and considered the AV FOI (Figure S2 ). This procedure
was repeated during atrial pacing at 10 beats/min above spontaneous
sinus rhythm. Afterwards, the interventricular (VV) interval was
adjusted by programming the one that achieved the shortest QRS
(simultaneous RV and LV pacing [VV 0 ms], 30 ms LV pre-excitation,
and 30 ms RV pre-excitation). These VV intervals were chosen because
previous studies indicated that most patients showed the best VVs in
this range.7,10 The VV value that achieved the
narrowest QRS was considered the VV FOI.
Combined MPP-FOI strategy: The AV and ∆1 (RV-LV2) intervals were
optimized as in the FOI method. Using the pacing vectors LV1 and LV2
obtained for the MPP strategy, ∆2 was ultimately programmed to 5 ms
(minimum programmable delay).
c) Electrocardiographic imaging
The biventricular activation time was evaluated using ECGI recordings
(CORIFY Care SL) obtained while running four programming configurations:
(1) intrinsic rhythm, (2) MPP, (3) SPP-FOI, and (4) MPP-FOI.
The torso surface potential was obtained using body surface potential
mapping, wherein 64 electrodes attached to the skin were recorded at a
sampling rate of 1000 Hz for off-line processing. Electrode location and
torso and heart volumes were determined based on (1) cardiac images
acquired via computed tomography or magnetic resonance imaging obtained
before device implantation and (2) photogrammetry techniques that enable
3D reconstruction of the torso from a standard video recording.
An average PQRST interval was calculated for each lead using template
matching averaging after removing pacing artifacts. An inverse computed
electrogram was reconstructed for the heart’s surface by solving the
inverse problem using zero-order Tikhonov and L-curve
methods.15
The biventricular activation time was calculated by (1) a set of
sinusoidal wavelets for all time instants with a negative slope within
the QRS complex and with an amplitude proportional to the slope at that
time and (2) the instantaneous phase of Hilbert’s transform of a
composite signal of all sinusoidal wavelets. The activation times
corresponded to the points where phase inversions occurred in that
instantaneous phase. The total biventricular activation time was defined
as the difference between the last and first activation times.
d) Echocardiographic measurements
An echocardiography specialist blinded to device programming obtained
standard Doppler echocardiographic images using a commercially available
system (Vivid 7; General Electric, Milwaukee, WI, USA).
Each patient was evaluated at baseline (device in OFF) and with each
pacing configuration (MPP, SPP-FOI, and MPP-FOI). Cardiac asynchrony was
evaluated at several levels: (1) left intraventricular asynchrony using
septal flash16 and 2D strain, (2) AV asynchrony using
the diastolic filling ratio (diastolic filling time/RR interval
duration),17 and (3) VV asynchrony quantified as the
difference between the LV and RV pre-ejection times with pulsed-wave
Doppler (Figure S3 ).18 In the 2D strain
analysis, the time difference between the peak systolic strain at
opposing LV walls (mid-septal and mid-lateral) was measured. Finally,
the LV outflow tract velocity time integral, a measure of cardiac
systolic function, was quantified.
e) Estimated battery longevity
At 45 days post-implantation, data for estimating battery longevity with
the final programmed configuration (MPP, SPP-FOI, or MPP-FOI) were
collected, and estimated battery life was compared between patients who
had MPP and SPP activated. Right atrial and RV pacing outputs were
programmed at 2.5 V/0.5 ms, and LV pacing output was programmed at 1.5
times the pacing threshold.