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\begin{document}

\title{The Impact of Leadless Pacemaker on the Development of Pacemaker induced
Cardiomyopathy and Tricuspid Regurgitation, A Retrospective Analysis}



\author[1]{David Kerling}%
\author[1]{Adam Kisling}%
\author[1]{Andrew Heroy}%
\author[1]{Thomas Arnold}%
\author[1]{Mark Haigney}%
\author[1]{Matthew Needleman}%
\affil[1]{Walter Reed National Military Medical Center}%


\vspace{-1em}



  
  \date{May 20, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
\textbf{Introduction:} Leadless pacemakers (LPs) have been suggested to
have a lower incidence of pacemaker induced cardiomyopathy (PICM)
compared with transvenous systems. LPs have also been suggested to cause
less frequent and less severe tricuspid valve regurgitation (TVR) when
compared to traditional transvenous pacemakers (TVPs). Given limited
research in this field, our study aims to better understand the
incidence of PICM and TVR in patients with a LP and the factors that
affect these incidences. \textbf{Methods:} The study comprised of
patients within the National Capital Region Military Health System who
received a Medtronic Micra LP from 2017 to 2021 and had a pacing
percentage of \textgreater{}20\%. Pre-procedural and follow-up
echocardiograms were retrospectively assessed to determine the change in
left ventricular ejection fraction (LVEF) and the degree of TVR. Given
the known impact of the PICM definition on the reported incidence, we
assessed rates of PICM using two distinct definitions, 1.) [?]10\%
decrease in LVEF or 2.) [?]10\% decrease in LVEF to an LVEF of
\textless{}50\%. We also assessed the pacemaker implantation location
and the change in QRS duration after implantation and pacing.
\textbf{Results:} The study included a total of 48 patients. The average
age of patients in the study was 77, with 67\% males. The most common
reason for LP implantation was complete AV block (38\%). Pacemaker
locations included high (13\%), mid (31\%), and apical septum (56\%).
The mean time interval between pacemaker implantation and follow up
echocardiogram was 697 days (SD 460). A total of 5 patients (12.5\%) met
definition 1 for PICM and 3 patients (6.25\%) met definition 2. TVR was
graded to be more severe than baseline in 37\% of patients, unchanged in
32\%, and improved in 30\%. The average change in QRS duration after
pacing was an increase of 46ms with an average QRS duration of 159ms at
follow-up. \textbf{Conclusion:} Compared to commonly reported incidences
of PICM, LPs appear to have a significantly lower rate of PICM,
regardless of the PICM definition used, increase in QRS duration, or
implantation location. In this study, LPs did not statistically
significantly impact TVR severity.%
\end{abstract}%



\sloppy


\textbf{The Impact of Leadless Pacemaker on the Development of Pacemaker
induced Cardiomyopathy and Tricuspid Regurgitation, A Retrospective
Analysis} \textbf{Authors: David Kerling MD, Adam Kisling MD, Andrew
Heroy, Thomas Arnold, Mark Haigney MD, Matthew Needleman MD FHRS} 11All
research participates are affiliated with Walter Reed National Military
Medical Center and this is the location of where the research was
conducted\textbf{Abstract Introduction:}Leadless pacemakers (LPs) have
been suggested to have a lower incidence of pacemaker induced
cardiomyopathy (PICM) compared with transvenous systems. LPs have also
been suggested to cause less frequent and less severe tricuspid valve
regurgitation (TVR) when compared to traditional transvenous pacemakers
(TVPs). Given limited research in this field, our study aims to better
understand the incidence of PICM and TVR in patients with a LP and the
factors that affect these incidences.\textbf{Methods:}The study
comprised of patients within the National Capital Region Military Health
System who received a Medtronic Micra LP from 2017 to 2021 and had a
pacing percentage of \textgreater{}20\%. Pre-procedural and follow-up
echocardiograms were retrospectively assessed to determine the change in
left ventricular ejection fraction (LVEF) and the degree of TVR. Given
the known impact of the PICM definition on the reported incidence, we
assessed rates of PICM using two distinct definitions, 1.) [?]10\%
decrease in LVEF or 2.) [?]10\% decrease in LVEF to an LVEF of
\textless{}50\%. We also assessed the pacemaker implantation location
and the change in QRS duration after implantation and
pacing.\textbf{Results:}The study included a total of 48 patients. The
average age of patients in the study was 77, with 67\% males. The most
common reason for LP implantation was complete AV block (38\%).
Pacemaker locations included high (13\%), mid (31\%), and apical septum
(56\%). The mean time interval between pacemaker implantation and follow
up echocardiogram was 697 days (SD 460). A total of 5 patients (12.5\%)
met definition 1 for PICM and 3 patients (6.25\%) met definition 2. TVR
was graded to be more severe than baseline in 37\% of patients,
unchanged in 32\%, and improved in 30\%. The average change in QRS
duration after pacing was an increase of 46ms with an average QRS
duration of 159ms at follow-up.\textbf{Conclusion:}Compared to commonly
reported incidences of PICM, LPs appear to have a significantly lower
rate of PICM, regardless of the PICM definition used, increase in QRS
duration, or implantation location. In this study, LPs did not
statistically significantly impact TVR severity.\textbf{Keywords:}
Leadless Pacemaker, Pacemaker Induced Cardiomyopathy, Tricuspid Valve
Regurgitation



\textbf{MAIN TEXT:}

\textbf{Introduction:}

PICM is associated with a significantly increased risk of heart failure
hospitalization and all-cause mortality {[}1{]}. The incidence of
pacemaker induced cardiomyopathy PICM has been reported to be
approximately 10-15\%, with increased risk in patients with a wide paced
QRS duration and a high right ventricular pacing burden
(\textgreater{}20\%). The risk of PICM has also been suggested to be
higher in patients who are male, exhibit atrioventricular block as an
indication for PPM implantation, and have a previous history of
myocardial infarction, chronic kidney disease, and atrial fibrillation
{[}2 3{]}. Pacing mode has not been associated with an increased risk of
PICM. The reported incidence of PICM has also been dependent on how it
is defined in the given study. One recent meta-analysis of PICM
identified 15 unique definitions of PICM {[}1{]}. In that meta-analysis,
the pooled prevalence of PICM was 12\%. The reported incidence is
highest when PICM is defined as a LVEF decrease of [?]10\%. One recent
study showed that when PICM was defined as an LVEF reduction of [?] 10\%,
the reported incidence was 39\% {[}4{]}. The most commonly used
definition of PICM is a [?]10\% decrease in LVEF to an LVEF of
\textless{}50\% {[}3{]}. This second definition is the most stringent
but also provides the highest degree of confidence that a cardiomyopathy
has developed as a result of pacing. In one recent study, the incidence
of PICM was shown to be significantly less with LPs compared to TVPs
{[}5{]}. However, robust data is lacking. Our study attempts to better
understand the impact of LPs on left ventricular function by assessing
pre and post implantation LVEF and how this is related to tricuspid
regurgitation, LP septal implantation location, and paced QRS duration.

The development of and worsening underlying tricuspid valve
regurgitation has also been shown in patients with both TVPs and LPs.
Implantation of TVPs leads to moderate to severe TVR in 14-29\% of cases
and to worsening of baseline TVR in an even greater proportion of cases
{[}2 6-8{]}. The degree of TVR has been shown to increase with the
number of leads crossing the tricuspid valve, and the mechanisms of TVR
from pacemaker leads include valve obstruction caused by a lead placed
between leaflets, lead adherence due to fibrosis and scar formation to
the valve causing incomplete closure, lead entrapment in the tricuspid
valve apparatus, and valve perforation or laceration {[}6{]}. A recent
study containing 28 patients with a St. Jude Nanostim LP and 25 patients
with a Medtronic Micra LP showed worsening TVR by 1 or 2 gradations in
43\% of patients {[}9{]}. The same study also showed that those with a
more septal compared to apical position were five times more prone to
worsening TVR. Potential pathophysiologic explanations of worsening TVR
after LP include direct interaction of the LP with tricuspid valve
apparatus, valve damage during implantation, and ventricular
dyssynchrony. However, the incidence of TVR attributable to LP
implantation in that study was unexpectedly high. Our study attempts to
better understand the impact of LPs on the frequency and severity of TVR
independent of and relative to septal location.

\textbf{Methods \& Materials:}

Patient Selection

The inclusion criteria for this study were the implantation of a
Medtronic Micra LP with pre-procedural and post-procedural
echocardiographic evaluation and a pacing percentage greater than
twenty. Patients with a history of cardiac resynchronization therapy,
those who did not meet pacing threshold, and lack of interval follow up
data were excluded from the study. One patient was excluded due to lack
of data for device implantation location, and one patient was excluded
due to a myocardial infarction and subsequent sudden cardiac arrest
within one week of his procedure which resulted in a decrease in LVEF
that was deemed not to be secondary to PICM. This sudden cardiac arrest
due to coronary thrombosis was determined not to be a procedural
complication. A total of exactly 200 patients in the National Capital
Region Military Health System received a Medtronic Micra LP from 2017 to
2021. Of these patients, 50 were being paced \textgreater{}20\% of the
time, which resulted in 48 patients being included in our analysis after
the two exclusions discussed above. 43 of these 48 patients had an
initial ejection fraction of [?] 50\% and were evaluated for PICM with
both criteria while the remaining 5 patients were evaluated for PICM
under the first criteria only.

Study Population

Forty-eight patients fulfilled the inclusion criteria and were included
in the final analysis. The average age in this study was 76.62 with a
standard deviation of 13.29 (Table 1). Men made up 67\% of the
population, and Caucasians made up 71\% of the population. The two most
common comorbidities were hypertension and hyperlipidemia.

\textbf{Table 1.}

Baseline Demographics\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Characteristic & N (\%) and/or (SD)\tabularnewline
Age & 76.62(13.29)\tabularnewline
Gender &\tabularnewline
\emph{Female} & 16 (33\%)\tabularnewline
\emph{Male} & 32 (67\%)\tabularnewline
Race &\tabularnewline
\emph{White} & 34 (71\%)\tabularnewline
\emph{Black} & 10 (21\%)\tabularnewline
\emph{Hispanic} & 2 (4.2\%)\tabularnewline
\emph{Other} & 2 (4.2\%)\tabularnewline
Mode &\tabularnewline
\emph{VVIR} & 29 (60\%)\tabularnewline
\emph{VDD} & 13 (27\%)\tabularnewline
\emph{VVI} & 5 (10\%)\tabularnewline
\emph{VDI} & 1 (2.1\%)\tabularnewline
Indication &\tabularnewline
Complete AV Block & 18 (38\%)\tabularnewline
\emph{Afib with bradycardia or pauses} & 15 (31\%)\tabularnewline
\emph{Symptomatic Afib failing rate/rhythm control} & 11
(23\%)\tabularnewline
\emph{Atrial flutter with bradycardia or pauses} & 3
(6.3\%)\tabularnewline
\emph{Symptomatic bradycardia} & 1 (2.1\%)\tabularnewline
Location &\tabularnewline
\emph{apical septum} & 27 (56\%)\tabularnewline
\emph{mid septum} & 15 (31\%)\tabularnewline
\emph{high septum} & 6(13\%)\tabularnewline
Comorbidity &\tabularnewline
\emph{Prior Leadless Pacemaker} & 1 (2.1\%)\tabularnewline
\emph{Prior pacemaker} & 1 (2.1\%)\tabularnewline
\emph{Heart Failure} & 24 (50\%)\tabularnewline
\emph{Hypertension} & 43 (90\%)\tabularnewline
\emph{Diabetes} & 19 (40\%)\tabularnewline
\emph{CAD} & 25 (52\%)\tabularnewline
\emph{Prior Myocardial infarction} & 1 (2.1\%)\tabularnewline
\emph{Prior CABG} & 4 (8.3\%)\tabularnewline
\emph{Atrial Fibrillation} & 36 (75\%)\tabularnewline
\emph{Atrial Flutter} & 18 (38\%)\tabularnewline
\emph{Sinus Node Dysfunction} & 11 (23\%)\tabularnewline
\emph{AV Conduction Defects} & 29 (60\%)\tabularnewline
\emph{Hyperlipidemia} & 42 (88\%)\tabularnewline
\emph{Obesity} & 16 (33\%)\tabularnewline
\emph{CKD} & 18 (38\%)\tabularnewline
\emph{COPD} & 6 (13\%)\tabularnewline
\bottomrule
\end{longtable}

Device Characteristics

During implantation of all LPs and the follow-up period, there was no
evidence of major adverse cardiovascular events or other device related
complications.

Indications for device placement are included in Table 1, with the most
common indication being complete AV block (38\%). Patients were either
implanted with a Medtronic Micra AV (44\%) or Micra VR device (56\%).
The septal location, as determined from chest x-ray, with the highest
number of implantations was the apical septum with 27 (56\%), followed
by the mid septum with 15 (31\%) and the high septum with 6 (13\%)
(Figure 1). Using posterior-anterior and lateral chest x-ray
projections, a device was labeled apical if located in the anterior
1/3\textsuperscript{rd}, mid if located in the middle
1/3\textsuperscript{rd}, and high if located in the basal
1/3\textsuperscript{rd} of the septum. The devices were most commonly
programmed to the VVIR mode (Figure 3). VDD pacing mode consisted of
27\% while VVI/VVIR consisted of 71\% of patients. The average pacing
burden was 82.89\% (STD 22.33), ranging from 22.6\% to 100\%.

Data Collection

The data for this study was obtained by a retrospective chart review of
a prospectively maintained database for Medtronic devices. Data
collected in this retrospective chart review included baseline
demographics, relevant clinical characteristics, echocardiographic data
(pre-implantation and post-implantation visual LVEF, biplane LVEF, and
tricuspid valve regurgitation severity), LP septal implantation location
based on post-procedure chest x rays\textbf{,} and QRS duration based on
12-lead electrocardiogram pre-implantation and while paced\textbf{.}

Primary and Secondary Outcome

The primary outcome that we assessed was the development of PICM. Given
the absence of an agreed-upon definition of PICM, we analyzed the
incidence of PICM using two separate definitions: 1.) LVEF decrease of
[?]10\% and 2) [?]10\% decrease in LVEF to an LVEF of \textless{}50\%. The
first definition commonly reports the highest incidence, and the second
is the most referenced in the literature {[}3{]}. As a secondary
outcome, we also assessed for worsening of tricuspid regurgitation based
on echocardiographic data. When tricuspid regurgitation was present, the
severity was reported from mild to severe, consistent with American
Society of Echocardiography guidelines. Other secondary outcomes
assessed were the effect of device implantation location on the LVEF and
the effect of device implantation on QRS duration.

Implantation Procedure

Our approach to LP implantation follows the manufacturer's recommended
implantation technique. Ultrasound-guided femoral access was obtained,
and an 8F femoral sheath was placed in the femoral vein. Through the
femoral sheath, a wire was inserted into the femoral vein, and
fluoroscopy was used to confirm the appropriate access. A right
ventricular angiogram was then performed through an angled pigtail
placed in the right ventricle. An intermediate-sized dilator was used to
increase the venotomy size. The Medtronic Micra implantation sheath with
dilator was then inserted over a stiff wire into the right atrium, and
the dilator was removed. The device and delivery system were then
flushed and checked for malfunctions. The device and delivery system
were then inserted into the implantation sheath. Multiple fluoroscopy
views and ventriculography were used to confirm appropriate implantation
site selection. Once an appropriate location was reached, the device was
deployed. Impedance, injury pattern, and capture thresholds were
measured to confirm that the implantation location was adequate, and the
device was repositioned if needed. Once the device was confirmed to be
securely in place, the delivery system was removed, and hemostasis was
achieved with a figure-of-eight stitch and manual pressure.

Statistical Analysis

A Paired T-Test was performed to test for a significant difference in
group means of preprocedural LVEF and postprocedural LVEF. This section
of analysis was done to determine if the mean ejection fraction was
significantly different after the procedure. A Wilcoxon Signed-Rank Test
was performed to see if the distribution of the before and after LVEF
were symmetric about zero.

We then set out to determine if the location of the Micra had any
significance in EF performance. Before performing our two-way ANOVA to
test the significance of the group (implantation location) means in each
of the EF states (before and after), we had to confirm homoscedasticity
(homogeneity of variance), which would confirm that the variance around
the mean was roughly equal in all groups. For this purpose, we employed
the Bartlett Test, which confirmed that there was roughly equal variance
in the before and after LVEF groups. We were then able to perform a
two-way ANOVA test, an ANCOVA test, and a Fixed Effects Model to
determine if the Micra implantation location had any significant effect
on the LVEF.

Basic statistical analysis was also used to evaluate the impact of
device implantation on the QRS, TR severity, and occurrence of PICM.

\textbf{Results:}

The results of our analysis of the population's raw outcomes data are
presented in Table 2. Note that the fifth data column shows that not
every patient had data in every category, but all 48 patients had pacing
data and a pre-procedure and post-procedure visual LVEF. The mean
interval between pacemaker implantation and the follow up echocardiogram
was 696.83 days. On average, patients were paced 82.89\% of the time.
Only 6 patients per paced less than 50\% of the time. The average LVEF
change was an increase of 0.23\% (STD 8.93).

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/696741/articles/685105-the-impact-of-leadless-pacemaker-on-the-development-of-pacemaker-induced-cardiomyopathy-and-tricuspid-regurgitation-a-retrospective-analysis}

\textbf{Table 2:}

Raw outcomes data for patient device characteristics and pre- and post-
implantation EF and QRS difference.

Primary Outcome

Analysis of the LVEF data was performed for the entire dataset as well
as for each implantation location group (Figure 1). The mid septum group
shows the greatest variation, while the high septum placement had the
least variation, although that group also had the lowest population
size. There are a few data points on the higher and lower LVEF's that
could be considered outliers in this dataset. Therefore, secondary
analysis was run with those points removed to see if results were any
different, but the results were not altered. There was one subject whose
age was 14 and whose ejection fractions before and after were 76 and 77
respectively. Although this patient's LVEF was dissimilar to the rest of
the study population which consisted of elderly adults, the focus of
this study was to determine the incidence of PICM after LP implantation,
so the patient was included.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 1A:} Visually estimated LVEF before and after
implantation without any grouping based on device location. The
correlation coefficient is 0.43, p \textless{}0.01. The histograms of
frequencies of pre- and post-ejection fractions are displayed above and
to the right of the scatterplot.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 1B:} Visually estimated LVEF before and after
implantation for each of the device location groups plotted with a
regression for each group.

Five patients had an initial LVEF of \textless{}50\% but were included
in the analysis given that our first definition of PICM allowed for an
initial LVEF of \textless{}50\%. Five patients (10.4\%) met the criteria
for definition 1 of PICM, and three patients (7.0\%) met the criteria
for definition 2 of PICM. For the three patients who met the criteria
for definition 2, their mean visually estimated LVEF was 55\% before
implantation, and their LVEF decreased by 18\% on average.

The Paired T-Test resulted in an F-statistic of -0.1778 (P value:
0.8596) which demonstrates that the difference in LVEF before and after
the device implantation was not significant. The Wilcoxon Signed-Rank
Test resulted in an F-statistic of 182.0 (P value: 0.8661) which
demonstrates that the LVEF distributions before and after the device
implantation were symmetric.

Secondary Outcomes:

\emph{Implantation Location}

After the Bartlett Test showed that the LVEF pre-procedure and LVEF at
follow-up had roughly equal variance with a P-value of 0.0457, the
Two-Way ANOVA showed an elevated P-value of 0.993 (greater than the
significance level of 0.05), which means that there is no significant
difference between the pre-implantation and the post-implantation LVEF
means of the 3 locations or an interaction between the location and the
pre/post-implantation LVEFs.

This leads us to another important finding. The group means for LVEF
pre/post-implantation were~exactly~equal in the mid and high septum
locations (Table 4 and Figure 2). This was not an error in our
statistical analysis because the standard deviations for these two
groups were different.

\textbf{Hosted file}

\verb`image4.emf`  available at \url{https://authorea.com/users/696741/articles/685105-the-impact-of-leadless-pacemaker-on-the-development-of-pacemaker-induced-cardiomyopathy-and-tricuspid-regurgitation-a-retrospective-analysis}

\textbf{Table 4:}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Figure 2:}

Mean LVEF before and after device implantation

Finally, we performed ANCOVA and Fixed Model assessments on the
implantation locations and their associated LVEFs. These analyses
confirmed that implantation locations were not significant when looking
at ejection fraction before and after implantation in our study
population.

\emph{Tricuspid Valve Regurgitation}

Our analysis of TVR was somewhat limited by 1 of our patients not having
any TVR data included in his pre-procedural echocardiogram and 4
patients not having any TVR data included in their follow-up
echocardiograms. For the purposes of statistical analysis, TVR was
graded as none, mild, mild-moderate, moderate, moderate-severe, and
severe as described in the echocardiogram reports, and these grades were
converted to numerical values with 0 representing no TVR and 5
representing severe TVR. Of the 43 patients who were able to be assessed
for the effect of their LP on TVR, none of the patients had severe TVR
pre-procedurally, and 1 patient was found to have severe TVR on their
follow-up echocardiogram (Figure 3). 33\% of patients had no change in
the TVR grade, 28\% had an improvement by 1 grade, 2\% improved by 2 or
more grades, 23\% worsened by 1 grade, and 14\% worsened by 2 or more
grades. The average change was an increase in TVR by 0.28 grades.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Figure 3:} Grade of TVR in patients before and after LP
implantation

The average change for the entire study population was an increase in
TVR by 0.28 grades. However, subgroup analysis by LP implantation
location revealed that the average increase in TVR was 0.04 grades, 0.25
grades, and 0.67 grades for the apical septum, high septum, and mid
septum locations respectively.

\emph{QRS Duration}

Sixty-five percent of patients in this study had documented QRS
durations before and after implantation. The average increase in QRS was
37.48 ms with a standard deviation of 38.00 ms. The greatest increase in
QRS duration was 103 ms. The greatest decrease in QRS duration was 38
ms, which may be explained by conduction system pacing. The data did not
implicate an implantation location that was associated with
significantly less QRS duration lengthening. The pre-implantation and
post-implantation QRS duration correlation coefficient for the entire
dataset regardless of implantation location was 0.02, and correlation
coefficients were similar when individual implantation location groups
were assessed. This demonstrates that, although there is typically an
increase in QRS duration after pacing is initiated, it is not possible
to predict prior to implantation which patients will have significant
increases in QRS duration.

\textbf{Discussion:}

PICM Definition and Left Ventricular Function

In the present study, we evaluated the impact of leadless pacing on left
ventricular ejection fraction. Overall, there was no change in mean LVEF
in our cohort of 48 subjects with LPs at 697 day follow up. We assessed
the incidence of PICM in leadless pacemakers using both a liberal
definition (Definition \#1; drop in LVEF \textgreater{}10\%) which has
been reported to result in a PICM incidence of up to 39\% in TVPs and a
stringent definition of PICM (Definition \#2; drop in LVEF
\textgreater{}10\% and mean LVEF \textless{}50\%) which has been
reported to result in a PICM incidence of approximately 13\% {[}3{]}.
The main finding of our study was an incidence of PICM in our study of
LPs of 10.4\% using Definition \#1 and 7.0\% using Definition \#2.

Sanchez et al recently compared the incidence of PICM in 131 patients
with TVPs and 67 patients with LPs who were all pacemaker-dependent. it
was shown that LPs lead to significantly less PICM than TVPs, with a
rate of 3\% with LP and 13.7\% with TVP {[}5{]}. That study used a
definition for PICM which we have referred to as definition 2 in this
study. The 13.7\% incidence of PICM in the TVP group is similar to the
typical published incidence as discussed above, which supports the
validity of that study.

The etiology of PICM is commonly attributed to dyssynchronous right and
left ventricular electromechanical activation which may also induce
changes in coronary blood flow, hemodynamics, fibrosis, perfusion, and
metabolism {[}10{]}. Some have suggested that this dyssynchrony could be
reduced if the pacing lead is placed more basally on the septum, given
studies showing higher rates of PICM with apical pacing {[}4{]}. The
idea is that with a basally-placed LP, the capture of more proximal
conduction tissue could result in a narrowed QRS complex and improve
ventricular synchrony, as seen in conduction system pacing {[}11{]}. No
other studies to our knowledge have assessed the impact of LP septal
implantation location on LVEF. However, even in studies with TVP, the
data is mixed, with some studies noting an increased risk of PICM in
apical vs septal pacing {[}12{]} {[}13{]}, while another study showed no
association {[}14{]}.

Our results are not consistent with the idea that a more basal location
of the LP would result in less PICM as a result of the capture of the
early conduction system, given that there was no statistically
significant relationship identified between changes in LVEF and the QRS
duration change or the LP implantation location. Although our study did
not include a direct comparison group of patients with TVPs, the lower
incidence of PICM in LPs could be explained by differences in myocardial
activation at the level of the septum as well as the effects of
tricuspid valve function as described below.

Tricuspid Regurgitation

Tricuspid regurgitation (TVR) is a well-documented complication of both
TVPs and LPs. A study assessing the impact of LPs on atrioventricular
valve function over a 12-month period showed TVR to be graded more
severe in 43\% of patients as discussed above {[}9{]}. Compared to the
mechanisms of TVR due to TVPs discussed above, potential mechanisms for
TVR after LP implantation include valve damage during implantation,
chronic mechanical interaction of the device with the valve or sub
valvular apparatus, or pacing-induced dyssynchrony resulting in
ventricular dysfunction and increased filling pressures {[}9 15{]}.
However, the degree of TVR worsening after LP implantation is likely
lower than after TVP implantation due to the difference in mechanism,
but the data on TVR after LP implantation is not robust.

Unlike PICM, the degree of RV pacing has not been shown to correlate
with new onset or worsening TR in TVPs. Additionally, a recent study of
patients with LPs showed no evidence of worsening TVR in the first 2
months post-implantation, making it unlikely that damage during
implantation is a major contributor to worsening TVR in this population
{[}16{]}. A recent study showed a 15\% increase in the odds for worse
TVR for each 1mm increase in distance between the LP and the tricuspid
valve annulus {[}15{]}. The likely mechanical impact of the LP on TVR
may be due to more chronic fibrotic changes that interfere with the
chordae tendineae, sub-valvular apparatus, or valve more directly.

The change in the degree of tricuspid valve regurgitation was highly
variable in our study with TVR graded to be more severe than baseline in
37\% of patients, unchanged in 32\%, and improved in 30\%. Additionally,
the average change was an increase in TVR by 0.28 grades. As a result,
our study did not clearly show LP having a significant impact on TVR.
Statistical analysis revealed no pattern of TVR that would predict
patients who were more likely to have worsening of their TVR
post-implantation.

Interestingly, though the LP implantation did not have a significant
effect on TVR severity overall, the average degree of TVR worsening was
higher in the mid septum group with an average increase in TVR by 0.67
grades. This is in comparison to the apical septum group which had an
average increase of only 0.04 grades. The study population is too small
to generate conclusions based on this pattern, but it could suggest that
implantation of LPs on the mid septum leads to increased interaction
with the tricuspid valve apparatus thereby leading to increased TVR.

Limitations

Major limitations to our study must be acknowledged. Our study was
retrospective, nonrandomized, and lacked a concurrent control group of
transvenously paced subjects. Our study may not have captured patients
who developed heart failure symptoms but did not present to our hospital
system.



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