DISCUSSION
This study shows, for the first time in a prospective study, the effects
of early activation of MPP on reverse remodelling, cardiac function and
clinical response in patients with heart failure treated with CRT. The
main findings of this study are (i) MPP was associated to a 6-month
response rate of 64.6% that did not meet at a 2.5% significance level
to be considered as significantly superior to current published CRT-D
literature (calculated at 57%), (ii) similarly to previous studies with
MPP, it was observed a numerically higher CRT response rate at 6 months
in subjects programmed using widest pacing cathodes (72%) compared to
other programming (61.1%), (iii) early activation of MPP was associated
with an important 6-month LV reverse remodelling and improvement in
cardiac function (i.e., LVEF) that was especially significant in
patients programmed using anatomical approach, (iv) clinical response to
early activation of MPP was high with only 12.2% of patients remaining
in class III at 6 months with a percentage of negative responders to CRT
according to the clinical composite score of 5%, and, (v) the incidence
of mortality and or all cause hospitalizations was low and significantly
lower in comparison with the observed in an recent cohort of patients
treated with CRT using quadripolar leads and conventional biventricular
pacing.
CRT by biventricular pacing is the only heart failure therapy that
improves cardiac function, functional capacity and survival while
decreasing hospitalizations14. Nevertheless, the
response to BiV pacing is variable, ranging from complete normalization
of cardiac function to lack of benefit. Suboptimal LV lead position,
with less possibilities to pre-excite late activated left ventricular
segments, and persistence of mechanical dyssynchrony despite
biventricular pacing have been some of the suggested reasons to explain
the absence of response to CRT4. The limited ability
of conventional pacing to reduce dyssynchrony in some patients could be
related to the important variability in the ventricular activation
pattern, even in patients with LBBB15,16. In
addition, the presence of diseased tissue and or lines of functional
conduction block in the LV can induce slow myocardial impulse
propagation or left ventricle latency, limiting the ability of a lateral
LV lead to reduce the mechanical dyssynchrony. Consequently,
intraventricular and interventricular dyssynchrony could persist in up
to 30% of patients during conventional biventricular
pacing4. MPP has been postulated to improve response
by depolarizing large segments of the LV simultaneously and therefore
activating early the area of latest electrical activation in left
ventricle. Consequently, MPP could reduce LV activation time improving
contractility and clinical outcomes.
Initial acute haemodynamic and echocardiographic studies of MPP showed a
significant increase in LV dp/dtmax, LV stroke volume
and a higher ability to reduce LV dyssynchrony in comparison to
conventional biventricular pacing5-8. Nevertheless,
the results observed in clinical trials have been somehow disappointing.
In the MPP IDE study, patients received biventricular pacing for 3
months and were then randomized to MPP or biventricular pacing for 6
months17. MPP met the primary efficacy endpoint
(non-inferiority of response rate based on Clinical Composite Score) in
this study. However, MPP was not superior to conventional biventricular
pacing reducing the percentage of patients with no response to CRT. In
the More CRT MPP study18, patients received
conventional biventricular pacing and those not responding at 6 months
were randomized to activate MPP or continue with biventricular pacing
for another 6 months. In this study, MPP was not superior to
biventricular pacing in the rate of conversion to echocardiographic
response to CRT (31.8% vs 33.8%, P = 0.72). Similarly, we did not
observe a significant benefit of MPP on the echocardiographic response
rate to CRT in comparison to the estimated value previously published
with conventional biventricular pacing.
Despite these neutral effects of MPP over the response rate to CRT, the
MPP IDE study showed that patients randomized to MPP and programmed to
pace from anatomically distant poles had a higher response rate to CRT
in comparison to pace from close MPP poles. The rate of clinical
responders at 9 months was 87% in the group of patients with the MPP
programmed with the anatomic separation in comparison to 65% observed
in patients with MPP and other programming or 70% in patients with
conventional biventricular pacing17. The MORE CRT MPP
study also observed a different non-responder to responder conversion
rate according to the selection of poles for MPP, 46% in patient with
the wide anatomical separation versus 26% in MPP and other programming
and 34% in conventional biventricular pacing18. In
our study, we also observed important differences in the effects of MPP
according to the selection of poles for MPP. The patients programmed
with an anatomical approach for MPP had a higher CRT response rate at 6
months (76%) compared to other programming (63%). Moreover, reverse
remodelling and improvement in cardiac function was especially important
in patients programmed using anatomical approach with a mean absolute
increase in LVEF of 14% in comparison to 8% in other MPP programming
group. Finally, the percentage of super-responders was 48% in patients
with MPP programmed using anatomical approach vs. 28% in other MPP
programming. The observed percentage of super responders in this group
is strikingly high in comparison to previous published data with
conventional biventricular pacing. Interestingly, the QUARTO II study
conducted by the same group using conventional biventricular pacing with
quadripolar leads reported a super-responder rate of
38%12.
These results are not surprising when considering the initial results of
MPP evaluating acute hemodynamic and immediate dyssynchrony reduction in
comparison to conventional biventricular pacing. These studies also
reported a superiority of an empiric method of selecting MPP vectors
based on maximizing anatomical spacing between pacing cathodes. These
studies also reported that pacing with the minimum delay between pacing
poles produced the best response in hemodynamics and dyssynchrony
reduction5-8. The MPP IDE and the MORE CRT MPP trials
also reported the highest benefits of MPP when pacing with the minimum
delay between MPP electrodes.
All of these observations may be in accordance with the suggested
benefits of MPP that entails the depolarization simultaneously of large
segments of the left ventricle, reducing its activation time and
resulting in a more efficient resynchronization. In this sense, wide
separation of the 2 pacing sites seems to be crucial to obtain a benefit
from MPP. When pacing sites are close, the area of initial myocardium
activation is smaller than the area activated from 2 widely separated
sites of pacing. Additionally, pacing from anatomically distant poles
increases the probability of stimulate early the of latest activated
area within the left ventricle and to avoid stimulation of overlying
myocardial scar from at least one of 2 cathodes during MPP. On the other
side, MPP by close pacing poles may be similar to conventional bipolar
CRT. Indeed, it has been shown with conventional bipolar LV leads
unwitting anodal capture in at least half of all
cases19. This cathodal-anodal pacing of 2 adjacent LV
lead poles may not be different from MPP from adjacent poles and would
explain the absence of benefit of MPP over conventional CRT when pacing
from narrow-spaced electrodes.
These results suggest the selection of widest-space electrodes with
simultaneous pacing when considering MPP activation to increase CRT
response. Otherwise, the probability of obtain a significant benefit
could be null with a negative impact over device battery longevity.
Clinical outcomes of MPP have been less studied. In a registry, Forleo
et al.20 showed that MPP was associated with a better
clinical outcome based on Clinical Composite Score, increased LVEF and
reduction in QRS duration compared to biventricular pacing. In MORE CRT
MPP study18, patients randomized to the MPP arm showed
a 21.8% reduction in heart failure events per 100 patient-years
compared to before randomization and the biventricular arm showed a
9.1% reduction compared to before randomization (P=NS). In our study,
we observed an important clinical response to MPP with only 12% of
patients remaining in class III at 6 months of follow-up and a
non-responder rate of 5% according to composite clinical score.
Moreover, at 6 months mortality was only 1.9% and 11.4% of patients
were admitted to the hospital for any reasons. Aiming to compare the
clinical outcomes of MPP to conventional biventricular CRT the QUARTO
III and QUARTO II cohorts were compared. Despite that groups were not
completely equivalent; QUARTO II and QUARTO III cohorts were
consecutives and were included, in most cases, by the same hospitals and
investigators what entails a homogeneous plan of treatment and
monitoring for the patients with heart failure involved in both studies.
We observed better clinical outcomes in the group of patients treated
with MPP with a significant reduction in the incidence of of mortality
and or all cause hospitalizations in comparison to conventional
biventricular pacing after adjusting for possible confounders variables.
Presently, MPP is available in devices from most of the companies.
Despite the absence of an undoubtedly evidence of benefit, clinicians
may have the opportunity of activating MPP in patients treated with CRT
and a capable device. The published evidence may indicate a potential
benefit from MPP only when it is possible to program wide separated
pacing poles. The results of this study are in line with this
observation and suggest a potential benefit in terms of clinical
outcomes.