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\begin{document}

\title{Left Atrial Appendage Remodeling after Atrial Fibrillation Ablation}



\author[1]{Yichi Zhang }%
\author[1]{Abdel Hadi El Hajjar}%
\author[1]{Chao Huang}%
\author[1]{Aneesh Dhore-Patil}%
\author[1]{Mario Mekhael }%
\author[1]{Charbel  Noujaim }%
\author[1]{Lilas Dagher}%
\author[1]{Alan Morris}%
\author[1]{Chan Ho Lim}%
\author[1]{Eugene Kholmovski}%
\author[2]{Raman Danrad}%
\author[1]{Tarek Ayoub}%
\author[1]{Christopher Pottle}%
\author[1]{Nassir Marrouche}%
\affil[1]{Tulane Medical Center}%
\affil[2]{Louisiana State University School of Medicine-New Orleans}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Introduction:} Larger left atrial appendage (LAA) ostium area
and greater left atrial (LA) volume have been associated with an
increased risk of ischemic stroke. Catheter ablation (CA) of atrial
fibrillation (AF) leads to morphological and functional changes within
the LA and LAA, some of which are not well studied. Here, we present
findings regarding post-ablation changes of the LAA ostia and correlate
them with various LA, LAA and left ventricular (LV) functional and
morphological metrics. \textbf{Methods}: This retrospective analysis
included patients scheduled to undergo first-time radiofrequency CA for
AF. Catheter ablation techniques included PVI with or without additional
ablations. Cardiac magnetic resonance imaging (CMR) was used to assess
LA, LAA and LV morphology and function, including LAA ostium area,
LA/LAA volume and volume index, LA ejection fraction, LA strain, and LV
ejection fraction. A Kruskal-Wallis test was used for correlating LAA
ostial dimensions with other LA morphological and functional metrics.
The t-test or two-sample Wilcoxon test were used to compare LA and LAA
morphological parameters. \textbf{Results}: A total of 101 patients with
AF were included in this study. The mean age was 60.1 \selectlanguage{ngerman}± 11.1 years, 69\%
were male, the average BMI was 29.22 ± 5.08. The LAA ostial area reduced
significantly from 3.84 ± 1.15 cm \textsuperscript{2} before ablation to
3.42 ± 0.96 cm \textsuperscript{2} after ablation (p=0.0004). This
reduction was asymmetrical, as the minor axis length decreased from 1.92
cm to 1.77 cm without significant changes in the major axis. LVEF
increased from a pre-ablation average of 48.26\% to a post-ablation
average of 53.62\% (p=0.015). Correlation of pre-ablation LVEF and LAA
ostium area showed a near-significant negative trend (r=-0.21, p=0.083).
LAEF correlated negatively with LAA ostial area (r=-0.289, p=0.0057),
total LA strain (r=-0.248, p=0.0185), and passive LA strain (r=-0.208,
p=0.049). \textbf{Conclusion:} There is a significant asymmetrical
reduction of the LAA ostial area after AF ablation that is independent
of LVEF changes. Larger LAA ostial area was associated with lower LAEF
and LA strain. Remodeling of the LAA after AF ablation may help account
for reduced risk of stroke and increased cardiac function.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Left Atrial Appendage Remodeling after Atrial Fibrillation
Ablation}

Yichi \emph{Zhang} BS\textsuperscript{1}, Abdel Hadi \emph{El
Hajjar}MD\textsuperscript{1}, Chao \emph{Huang} PhD\textsuperscript{1},
Aneesh\emph{Dhore-Patil} MD\textsuperscript{1}, Mario
\emph{Mekhael}MD\textsuperscript{1}, Charbel \emph{Noujaim}
MD\textsuperscript{1}, Lilas \emph{Dagher} MD\textsuperscript{1}, Alan
\emph{Morris}MS\textsuperscript{1}, Chan Ho \emph{Lim}
MS\textsuperscript{1}, Eugene\emph{Kholmovski} PhD\textsuperscript{1,2},
Raman \emph{Danrad}MD\textsuperscript{3}, Tarek \emph{Ayoub}
MD\textsuperscript{1}, Christopher \emph{Pottle} MS\textsuperscript{1},
Nassir \emph{Marrouche}MD\textsuperscript{1,\#}

\textsuperscript{1}TRIAD Center, Tulane University School of Medicine,
New Orleans, LA

\textsuperscript{2}Department of Biomedical Engineering, Johns Hopkins
University, Baltimore, MD

\textsuperscript{3}Lousiana State University School of Medicine, New
Orleans, LA

Corresponding Author:

Nassir F. Marrouche, MD

Professor of Medicine,

Director Heart and Vascular Institute

Tulane University School of Medicine

1430 Tulane Ave, New Orleans, LA, 70112.

nmarrouche@tulane.edu

\emph{Abstract:}

\textbf{Introduction:} Larger left atrial appendage (LAA) ostium area
and greater left atrial (LA) volume have been associated with an
increased risk of ischemic stroke. Catheter ablation (CA) of atrial
fibrillation (AF) leads to morphological and functional changes within
the LA and LAA, some of which are not well studied. Here, we present
findings regarding post-ablation changes of the LAA ostia and correlate
them with various LA, LAA and left ventricular (LV) functional and
morphological metrics.

\textbf{Methods} : This retrospective analysis included patients
scheduled to undergo first-time radiofrequency CA for AF. Catheter
ablation techniques included PVI with or without additional ablations.
Cardiac magnetic resonance imaging (CMR) was used to assess LA, LAA and
LV morphology and function, including LAA ostium area, LA/LAA volume and
volume index, LA ejection fraction, LA strain, and LV ejection fraction.
A Kruskal-Wallis test was used for correlating LAA ostial dimensions
with other LA morphological and functional metrics. The t-test or
two-sample Wilcoxon test were used to compare LA and LAA morphological
parameters.

\textbf{Results} : A total of 101 patients with AF were included in this
study. The mean age was 60.1 \selectlanguage{ngerman}± 11.1 years, 69\% were male, the average
BMI was 29.22 ± 5.08. The LAA ostial area reduced significantly from
3.84 ± 1.15 cm\textsuperscript{2} before ablation to 3.42 ± 0.96
cm\textsuperscript{2} after ablation (p=0.0004). This reduction was
asymmetrical, as the minor axis length decreased from 1.92 cm to 1.77 cm
without significant changes in the major axis. LVEF increased from a
pre-ablation average of 48.26\% to a post-ablation average of 53.62\%
(p=0.015). Correlation of pre-ablation LVEF and LAA ostium area showed a
near-significant negative trend (r=-0.21, p=0.083). LAEF correlated
negatively with LAA ostial area (r=-0.289, p=0.0057), total LA strain
(r=-0.248, p=0.0185), and passive LA strain (r=-0.208, p=0.049).

\textbf{Conclusion:} There is a significant asymmetrical reduction of
the LAA ostial area after AF ablation that is independent of LVEF
changes. Larger LAA ostial area was associated with lower LAEF and LA
strain. Remodeling of the LAA after AF ablation may help account for
reduced risk of stroke and increased cardiac function.

\textbf{Keywords} : Atrial Fibrillation, Left Atrial Appendage, Atrial
Remodeling, Atrial Myopathy, Cardiac MRI

\emph{Background:}

Atrial fibrillation (AF) is the most common arrythmia in the US, with an
estimated prevalence of 1-2\% (1), which increases with age to 20\% in
patients in their 80s (2). One of the most feared complications in AF
patients is cardioembolic stroke (3), with studies suggesting case
fatality rates of up to 27\% (4). Thus, current guidelines for the
treatment of AF involve a dual-strategy of rate/rhythm control for
prevention of arrythmia, as well as oral anticoagulation (OAC) for
mitigation of stroke risk (5). Prior data suggested that rate control
was non-inferior to rhythm control (AFFIRM trial)(6), recently early
rhythm control is proving to improve outcomes (EAST-AF, EARLY-AF)(7, 8).
Catheter ablation of AF has proven to be a safe and effective strategy
in drug-refractory AF patients. Recent trials have suggested that
ablation is superior to medication for reducing mortality in certain
subsets of AF patients (9) and that the former may also provide better
quality-of-life (10). However, the effect of catheter ablation on LA/LAA
morphology and function is poorly understood (11).

The left atrium (LA) serves a complex ``trio'' of functions, working as
a reservoir, conduit, and booster pump at different points of the
cardiac cycle (12). The LA's relatively weaker contractility compared to
the left ventricle (LV) increases the possibility of blood stasis (13).
The left atrial appendage (LAA) is the most common source for the
formation of systemic thromboemboli due to its unique shape and
increased tendency for blood stasis (14).The entrance from the LA into
the LAA is the LAA ostium, which is usually defined by the coumadin
ridge superiorly and the left circumflex artery inferiorly (15). The LAA
ostium was initially studied and measured for developing techniques for
LAA occlusion (16), such as the use of ligation, clip or a Watchman\selectlanguage{english}
device (17). However, detailed evidence is lacking on how baseline LAA
ostium characteristics are correlated with other anatomical and clinical
parameters of the LA and LAA in AF patients. Furthermore, there is a
paucity of data on how the LAA ostium changes after AF ablation. These
findings can help us better understand underlying mechanisms of LA/LAA
morphological changes following catheter ablation.

In this study we aim to assess baseline LAA ostium characteristics among
AF patients and correlate them with anatomical and functional parameters
of the LA and LAA, as well as patients' preexisting comorbidities and
risk factors. We will also be the first to report changes in the LAA
ostium following AF catheter ablation.

\emph{Methods:}

This is a retrospective observational study of AF patients who underwent
catheter ablation at Tulane Medical Center. All patients were treated
according to the current guidelines with rate/rhythm control and OAC.
Patients who were scheduled for catheter ablation received pre-ablation
cardiac magnetic resonance imaging (CMR) to ascertain LA fibrosis, LA
and LAA anatomical and functional characteristics as well as left
ventricular ejection fraction (LVEF). Catheter ablation techniques
included PVI with or without additional ablations. Additional ablation
lines were left to the discretion of the treating physician. A subset of
patients who completed AF ablation also underwent another CMR study
approximately three months to one year after their procedure to
re-assess LA and LAA anatomical and functional parameters and associated
changes post-ablation. All relevant baseline demographic information,
past medical history, current clinical parameters, and imaging
characteristics were collected and stored in a HIPAA compliant, secure
database for analysis. The Tulane university institutional review board
approved this study (IRB \#2019-1803).

\emph{CMR Study Protocol:}

All patients underwent a CMR study on a 1.5 Tesla clinical MR scanner
(Ingenia, Philips Healthcare). CMR protocol included Cine MRI of LA and
LV, and 3D late gadolinium enhancement (LGE) scan. Cine MRI was
performed in axial plane for LA and short axis plane for LV using a
retrospective ECG-gated balanced steady-state free precision (bSSFP)
pulse sequence. Cine scan for LA covers the whole LA and LAA by a stack
of contiguous 2D axial slices with thickness of 7.0 mm and spatial
resolution of 1.56x1.74 mm. The other scan parameters for this Cine scan
were repetition time (TR) = 2.80 ms, echo time (TE) = 1.40 ms, flip
angle (FA) = 60\textsuperscript{o}. Cine scan of LV covers the whole LV
by a stack of 2D short-axis slices with thickness of 8.0 mm, inter-slice
gap of 0.8 mm, spatial resolution of 1.45x1.65 mm. The other scan
parameters for Cine of LV scan were TR = 3.48 ms, TE = 1.74 ms, FA =
90\textsuperscript{o}. Scan protocol for 3D LGE was similar to 3D LGE
protocol optimized and validated in DECAAF and DECAAF II multi-center
studies (18). LGE scan was initiated 20-25 minutes after contrast agent
administration using a 3D inversion recovery prepared, respiration
navigated, ECG-gated, spoiled gradient echo pulse sequence. 3D LGE
imaged axial slab covering LA and LAA with spatial resolution of
1.25x1.25x2.5 mm. The other scan parameters for 3D LGE were TR = 5.26
ms, TE = 2.58 ms, and FA = 20\textsuperscript{o}.

\emph{LA Image Segmentation:}

Left atrial wall was manually segmented by expert observers from the
LGE\selectlanguage{english}-MRI images using the Corview image processing software (MARREK, Salt
Lake City, UT). Briefly, the protocol for segmentation proceeded as
follows: first, the endocardial border of the left atrium was defined,
including the PV extensions, by manually tracing the left atrium\selectlanguage{english}-PV
blood pool in each slice of the LGE\selectlanguage{english}-MRI volume. Next, the endocardial
segmentation was morphologically dilated and then manually adjusted to
create an assessment of the boundary of the epicardial left atrium
surface. Finally, the endocardial segmentation was subtracted from the
epicardial segmentation to define a wall segmentation, which was
manually edited to exclude the mitral valve and PVs. The resulting left
atrial wall segmentation included the 3D extent of both the left atrial
wall and the antral regions of the PVs. Images that could not be
segmented or quantified due to poor contrast, blurred left atrial
boundaries, and presence of artifacts in left atrial region were defined
as poor quality.

\emph{LA Fibrosis Assessment}

Quantification of LA fibrosis was obtained using methods previously
described(19). The LA wall was segmented manually and regions of
fibrosis in LGE-MRI images were defined by an intensity threshold
determined by expert inspection. Fibrotic tissue is detected when its
intensity is two to three standard deviations above the mean of the
normal tissue intensity. A 3D LA fibrosis map was created using volume
rendering module in Corview software (Marrek Inc., Salt Lake City, UT).
Inter-observer and intra-observer reproducibility for this technique was
previously reported (17). Fibrosis was represented as the volumetric
percentage of left atrial wall enhancement.

\emph{LA Morphological and Functional Parameters Assessment:}

A stack of contiguous axial cine images covering LA and LAA was
acquired. Tissue-tracking approach was used to quantify LA strain and
phasic volumes from the cine images. Endocardial and epicardial LA
borders was defined at end-systole by a blinded operator. Using defined
borders in each view, the software tracked the LA myocardium in
subsequent frames. The operator validated the generated contours during
the cardiac cycle for quality control. Images with poor tracking were
excluded. In each frame, the LA volume was calculated. Maximum, minimum,
and pre-atrial contraction LA volumes (LAVmax, LAVmin, VPreA) were
extracted from volume curve. The point on the LA volume curve during
diastole just before the fast descent following a period of stability in
LA volume was defined as preatrial contraction volume. At that point,
the atrial strain rate was equal to zero. All measured volumes were
indexed to body surface area. The global longitudinal strain and strain
rate were calculated by averaging the strain values over whole LA.

The volumetric LA function parameters were calculated as follows:

Total LA EF (in \%) = {[}(LAVmax - LAVmin)/LAVmax{]}x100

Active LAEF (in \%) = {[}(VPreA - LAVmin)/ VPreA{]}x100

Passive LAEF (in \%) = {[}LAVmax - VPreA)/LAVmax{]}x100

\emph{LAA Morphological and Functional Parameter Assessment}

The morphology of the LAA was assessed from 3D LGE images using
particle-based modeling (PBM) for statistical shape analysis (SSA).
Briefly, after contouring and segmentation by trained observers, we
created a three-dimensional reconstruction of the LAA. SSA using
particle-based modeling was performed on the LAA reconstruction to
define the shape class. For LAA ostium measurements, we used three
planes on the CMR to define the ostium and estimate its maximal
diameter, minimal diameter, circumference, and surface area. The ostium
of the LAA was first defined on the transversal image by the plane that
connected between the base of the Coumadin ridge and the proximal left
circumflex artery. The cross-section of the LAA ostium was created from
orthogonal projections in the coronal plane. The maximum and minimum LAA
ostium diameters were measured from the sagittal image. The
circumference and surface area were then calculated and provided by the
software. Figure 1 shows the procedural steps for registration of the
pre- and post-ablation LGE-MRI images to ensure spatial alignment as
well as for measurement of the LAA ostium.

\emph{Statistical Analysis}

All statistical tests were two-sided with p\selectlanguage{english}[?]0.05. Descriptive statistics
such as mean (SD) for continuous variables and frequency (\%) for
categorical variables were reported for the study sample. Statistical
analysis was performed using SAS version 9.4 and STATA version 14. A
Kruskal-Wallis test was used for correlating LAA ostial measurements
with other LA morphological and functional metrics. The t-test or
two-sample Wilcoxon test were used to compare LA and LAA morphological
parameters in patients with or without certain comorbidities, depending
on normality of variable. The two-sample Wilcoxon test was also used to
compare pre- and post-ablation LAA ostial parameters.

\emph{Results:}

\textbf{Baseline Characteristics:}

A total of 101 patients with AF were included in the study. The mean age
was 60.1 +- 11.1 years, 69\% were male, the average BMI was 29.22 +- 5.08
and the average body surface area (BSA) was 1.83 +- 0.68
m\textsuperscript{2}. Of all patients, 23.8\% had heart failure with
reduced ejection fraction (HFrEF), 6.9\% had heart failure with
preserved ejection fraction (HFpEF), 46.5\% had hypertension (HTN), and
7.9\% had a history of stroke or other systemic thromboembolism (SSE).
33.7\% of patients underwent some form of cardioversion and 38.6\% had
failed a trial of antiarrhythmic therapy. The average left ventricular
ejection fraction (LVEF) was 48.85\%.

In terms of baseline left atrial characteristics, the mean LAVI was
38.66 +- 10.2 mL/m\textsuperscript{2} , the mean LA sphericity index was
73.6 +- 18.9, the mean LAA volume was 6.76 +- 4.47 mL, and the mean
fibrosis level was 15.51 +- 8.02\%. Left atrial appendage shapes were
categorized into the popular ``windsock'' (6.93\%), ``cactus''(5.94\%),
``chicken wing''(77.2\%) and ``cauliflower'' (9.90\%) categories (20).
The baseline characteristics of the LA, LAA, and LAA ostia in our study
cohort are given in Table 1.

\textbf{LAA Ostium Dimensions}

The average LAA ostium area was 3.32 +- 1.17 cm\textsuperscript{2}. When
accounting for BSA, the indexed mean LAA ostium area was 1.67 +- 0.56
cm\textsuperscript{2}/m\textsuperscript{2}. Since LAA ostia can be
approximated with a centroid with a major and minor axis, the average
major axis length was 2.44 +- 0.48 cm, the average minor axis length was
1.72 +- 0.34 cm, with the average perimeter at 6.35 +- 1.17 cm.

When exploring the relationship between the LAA ostia characteristics
and various risk factors and comorbidities, patients with HFrEF had a
significantly larger LAA ostial area than patients without HFrEF (3.88
vs. 3.20 cm\textsuperscript{2}, respectively, p=0.0148). This result
remained significant when comparing the LAA ostial area indexed by BSA
(1.89 vs. 1.60 cm\textsuperscript{2}/m\textsuperscript{2}, respectively,
p=0.0268). No statistically significant associations were found between
LAA ostial area and other risk factors or comorbidities. The analysis
results are presented in Table 2.

\textbf{Left Atrial Appendage Ostium Dimensions and its Association with
Left Atrial Morphological and Functional Parameters}

The LAA ostial parameters were further examined for their correlation
with LA and LAA morphological parameters. The LAA ostial area was shown
to have a moderate positive correlation with LA volume (r=0.31,
p=0.0017) and LAA volume (r=0.42, p\textless{}0.0001). LAA ostial area
was largest in patients with a ``cauliflower'' LAA shape morphology
(4.53 cm\textsuperscript{2} vs 3.30 cm\textsuperscript{2} {[}average of
other morphology classes{]}, p=0.011). No association was found between
LAA ostial area and LA sphericity, LAVI or LA fibrosis level.

LAA ostial parameters were also correlated with LA functional metrics.
Total LAEF correlated negatively with LAA ostial area (r=-0.289,
p=0.0057). Indexed LAA ostial area was also negatively correlated with
total LA strain (r=-0.248, p=0.0185), and passive LA strain (r=-0.208,
p=0.049). There was a trend for negative correlation between LAA ostial
and active LA strain, but this was not statistically significant
(p=0.064).

Analysis results correlating LAA ostial parameters with LA morphological
and functional markers are presented in Tables 3A/3B and 4,
respectively. A selection of correlation analysis results from this
analysis are also shown in Figure 2.

\textbf{Changes in Left Atrial Appendage Ostium Following Catheter
Ablation}

A subgroup analysis on 37 patients who underwent pre- and post-ablation
CMR studies was performed. On average, the post-ablation CMR was
performed at 49.6 +- 26.7 weeks after procedure day. The LAA ostial area
reduced significantly from 3.84 +- 1.15 cm\textsuperscript{2} before
ablation to 3.42 +- 0.96 cm\textsuperscript{2} after ablation (p=0.0004).
11 of the 37 patients (29.7\%) experienced a reduction in ostial size to
below 3.5 cm\textsuperscript{2}while the minor axis length of the LAA
ostia decreased from 1.92 cm to 1.77 cm after ablation (p=0.0004), the
major axis length did not demonstrate a significant reduction
(p=0.1139). Other LA and LAA structural and functional markers were also
examined in these patients and compared pre- and post-ablation. Other
parameters such as LA volume, LAA volume, LAEF and various components of
LA strain did not change significantly after ablation. This subgroup
analysis on pre- and post-ablation changes is given in Table 5.

Additional analysis was performed to examine LVEF change
pre-/post-ablation and its association with LAA ostium area. First, LVEF
increased from a pre-ablation average of 48.26\% to a post-ablation
average of 53.62\% (p=0.015). Correlation of pre-ablation LVEF and
pre-ablation LAA ostium area showed a near-significant negative trend
(r=-0.21, p=0.083). There was no correlation between the post-ablation
change in LVEF and the change in LAA ostium area (p=0.671). There was
also no correlation between the post-ablation change in LVEF and the
change in LAA ostium area (p=0.513). Results of this correlation
analysis are presented in Figure 3.

\emph{Discussion}

This is the first study to show that the LAA ostium reduces in size
after AF ablation, and that this change is markedly asymmetrical, with
the minor axis length shortening significantly more than the major axis
length. In addition, we found that AF patients with HFrEF had a
significantly greater LAA ostium areas than non-HFrEF patients. We also
shown that LAA ostium size was positively correlated with both LA and
LAA volume, and that patients with a ``cauliflower'' morphology of the
LAA had significantly larger LAA ostia area than patients with other
morphologies. Taking a functional perspective, the LAEF, as well as
total and passive LA strains decreased as the LAA ostium size increased.
LVEF increased significantly after ablation but changes in LVEF after
ablation did not correlation with changes in LAA ostium area after
ablation.

Of all the comorbidities analyzed, only HFrEF correlated significantly
with LAA ostium size. This can be hypothesized to be due to stretching
of the LAA ostium over time secondary to volume overload seen in heart
failure(21). Both LA volume(22) and LAA volume(23) increases in patients
with heart failure, and both LA enlargement(24) and LAA enlargement(25)
is correlated with increased stroke risk. Another consideration
originates from findings of the CASTLE-AF trial, which showed the
superiority of ablation vs. medical therapy among AF patients with
comorbid heart failure (22). The trial showed that the hazard ratio for
stroke in these patients was 0.46 in favor of catheter ablation vs.
medical therapy. This supports our hypothesis that by reducing the LAA
ostial size, catheter ablation is also mitigating stroke risk in this
patient group. Future investigation should further elucidate the
underlying mechanisms for superiority of ablation when compared to
medical therapy in the heart failure population.

When correlating the LAA ostium area to other morphological metrics of
the LA and LAA, we found that the ``cauliflower'' LAA morphology was
associated with the largest ostial area. Previous studies have found
that ``single-lobed'', ``cauliflower'' LAA morphology and larger LAA
volume was associated with higher rates of stroke (26, 27). This finding
would be supported by the results of our investigation, as a larger LAA
ostium may confer a greater risk for thromboemboli generated in the LAA
of passing into systemic circulation (28). In addition, others have
reported that non- ``chicken-wing'' LAA morphologies were associated
with higher rates of stroke compared to the ``chicken-wing'' morphology
(29). However, contradictory findings have also been reported, stating
that stroke rates were similar across patients with different LAA
morphologies (30). Though most studies including ours used a two-expert
consensus in labeling LAA morphology, the relatively subjective nature
of this categorization demands for future revamping and improvement.

In addition to anatomical metrics, various LA functional metrics were
also found to be significantly associated with LAA ostium area.
Specifically, the LAA ostium area was negatively correlated with LAEF,
total LA strain and passive LA strain. While LAEF is more commonly used
as a surrogate for LA function (31), the three components of LA strain
may show a clearer picture and more thoroughly breakdown the role of the
LAA during the normal cardiac cycle and in AF. The total, passive, and
active components of LA strain correspond to the reservoir, conduit and
pumping functions of the LA, respectively (32). Our finding that the LAA
ostium area only correlates with total and passive LA strain may imply
that the LAA is mostly involved in the reservoir and conduit roles of
the atrium, but not necessarily in its pumping function. This is
supported by previous investigations that have characterized the LAA's
role as an overflow and decompression chamber for the LA (33). It is
also unsurprising that the LAA does not contribute significantly to the
LA pumping function, given its peripheral location, thin walls and
relatively weak contractility (34).

Finally, our study is the first to characterize changes in the LAA
ostium over time after AF ablation. Our hypothesis for the underlying
mechanism includes an ablation-induced chronic remodeling of the left
atrial substrate, which also includes changes to the LAA. The
termination of AF and restoration of sinus rhythm may allow atrial
myocytes to have more regular contractions and higher contractility(35).
Additionally, although there was a near-significant negative correlation
of pre-ablation LVEF and LAA ostium area, there was no direct
correlation found between post-ablation change in LVEF and change in LAA
ostium area. Furthermore, post-ablation change in LAEF also did not
correlate with change in LAA ostium area. These findings suggest that
the reduction in LAA ostium area seen after AF ablation is not a simple,
direct result of functional improvement of the LA or LV. Rather, this
reduction may be due to a more unique remodeling of the LAA in response
to specifically catheter ablation therapy. Interestingly, previous
studies have also found that a LAA ostium size \textless{}3.5
cm\textsuperscript{2} was associated with a reduced risk of stroke(36).
Although we did not find a direct correlation of LAA ostium area with
stroke in our study cohort, 29.7\% of our patients did experience a
significant reduction of LAA ostia from \textgreater{}3.5
cm\textsuperscript{2} to \textless{}3.5 cm\textsuperscript{2}. A
prospective, longitudinal study is needed to track stroke incidence in
this group.

Finally, the reduction in LAA ostium area observed in our patient cohort
was markedly asymmetrical, with significantly more shrinkage in the
minor axis length than the major axis length of the centroid. Without a
larger and more comprehensive study, the clinical implications of this
finding remain unclear. Although with the rising popularity of LAA
occlusion devices such as the Watchman\selectlanguage{english}, it may be beneficial to take
these post-ablation changes in the ostia into account when selecting the
appropriate device size. It will also be intriguing to explore the
underlying histology of LA myocytes surrounding the LAA ostium to
determine whether distinct features are present in cells that align in
the minor axis length direction. Lastly, it may be worth investigating
patients whose LAA ostium does not shrink in size after ablation, as
this cohort may exhibit an ``ablation-refractory'' phenotype and thus
suffer from higher stroke risk despite ablation. For this patient
cohort, LAA occlusion should be considered in addition to standard
anticoagulation therapy to mitigate stroke risk (37).

Our findings bear important and compelling clinical implications that
should be further explored in future investigations. Growing knowledge
of the LAA and the LAA ostium is crucial to our overall understanding of
AF pathophysiology and substrate stratification in AF management.

\emph{Limitations:}

Our study has several limitations. First, this is a retrospective study
that does not consider the implication of LAA ostial changes on clinical
outcomes. Therefore, we are currently following our patients' s cohort
prospectively to assess for stroke incidence and rates of other
complications. Second, only 37 patients in the cohort underwent
post-ablation CMR studies and were thus used to calculate changes in LAA
ostial size following catheter ablation. However, the reduction in
ostial size was nevertheless significant in this subgroup.

\emph{Conclusions}

After AF ablation, there is a significant asymmetrical reduction of the
LAA ostial area that was independent of LVEF and LAEF changes. LAA
ostial area was larger in patients with HFrEF, and in patients with
``cauliflower'' LAA morphology. Larger LAA ostial area was associated
with greater LA and LAA volume, and with lower LAEF and LA strain.
Remodeling of the LAA after AF ablation may help account for reduced
risk of stroke and increased cardiac function. Future studies are needed
to elucidate underlying mechanisms and explore clinical implications.

\emph{List of Abbreviations:}

LA: Left Atrium

LAA: Left Atrial Appendage

CA: Catheter Ablation

AF: Atrial Fibrillation

LV: Left Ventricle

PVI: Pulmonary Vein Isolation

CMR: Cardiac Magnetic Resonance

BMI: Body Mass Index

LVEF: Left Ventricular Ejection Fraction

MRI: Magnetic Resonance Imaging

OAC: Oral Anticoagulants

MRA: Magnetic Resonance Angiography

PC: Phase Contrast

LGE: Late Gadolinium Enhancement

bSSFP: Balance Stead-State Free Precision

LAV: Left Atrial Volume

HFpEF: Heart Failure with Preserved Ejection Fraction

HFrEF: Heart Failure with Reduced Ejection Fraction

BSA: Body Surface Area

HTN: Hypertension

SSE: Stroke and Systemic Embolism

LAVI: Left Atrial Volume Index

LAEF: Left Atrial Ejection Fraction

\emph{Declarations:}

\textbf{Ethics Approval and Consent to Participate:}

This study was reviewed and approved by the Tulane University School of
Medicine Institutional Review Board (2019-1803-TUHSC). Consent to
participate is not applicable.

\textbf{Consent for Publication:}

Not Applicable

\textbf{Availability of Data and Materials:}

The data that support the findings of this study are available from the
corresponding author, NM, upon reasonable request.

\textbf{Competing Interests:}

Dr. Marrouche reports receiving grant support and consulting fees from
Abbott, Wavelet Health, Medtronic, Biosense Webster, Boston Scientific,
GE Health Care, and Siemens, receiving consulting fees from Preventice,
and holding equity in Marrek Inc. and Cardiac Design. Dr. Kholmovski
reported receiving consulting fee from Marrek Inc. and holding equity in
Marrek Inc. All other authors have no conflicts of interest associated
with the content of this manuscript.

\textbf{Funding:}

Coherex contributed to the support of MRI analysists for this study.

\textbf{Authors' Contributions:}

YZ and NM established the study idea and designed the study. YZ, AHEH,
ADP, MM, CN, LD, EK, RD, and TA collected data for analysis. CH, AM, EK
and RD assisted with imaging acquisition and processing. CHL and CP
performed statistical modeling and produced figures and tables. YZ, AHEH
and CH drafted the initial version of the manuscript. All authors
participated in revisions of the manuscript and approved it for
submission and publication.

\textbf{Acknowledgements:}

We like to thank Ms. Agnieszka Jerzierska-Drutel, Dr. Arezu Bhatnagar,
Mr. Charles Kilgore, Ms. Monique Young, Ms. Monica Smith, Ms. Noor Makan
and other team members of the Tulane Heart and Vascular Institute for
their contributions.

\textbf{Tables and Figures}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\emph{Figure 1} : Procedure for Measurement of the LA and LAA Ostium.
(Abbreviations: LCX-Left Circumflex Artery)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\emph{\textbf{Figure 2}:} Correlation of Indexed LAA Ostium Area with
various important LA and LAA morphological and functional metrics.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\emph{\textbf{Figure 3}:} Correlation of LAA Ostium Area with LVEF.

Panel (A) shows the correlation of pre-ablation LAA ostium area with
LVEF. Panel (B) shows the correlation of the change in LVEF after
ablation with pre-ablation LAA ostium area. Panel (C) shows the
correlation of the change in LVEF after ablation with the change in LAA
ostium area after ablation.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{N=101} & Average & & Average\tabularnewline
\midrule
\endhead
Age (years) & 60.1 +/- 11.1 & LAVI (mL/m\textsuperscript{2}) & 38.66 +/-
10.2\tabularnewline
Male (\% of total) & 70 (69.3\%) & LA Sphericity Index & 73.6 +/-
18.9\tabularnewline
Female (\% of total) & 31 (30.7\%) & LAA Volume (mL) & 6.76 +/-
4.47\tabularnewline
BMI & 29.22 +/- 5.08 & Fibrosis (\% of LA wall) & 15.51 +/-
8.02\tabularnewline
BSA (m\textsuperscript{2}) & 1.83 +/- 0.68 & LAA Ostium Area
(cm\textsuperscript{2}) & 3.32 +1.17\tabularnewline
HFrEF (\% of total) & 24 (23.8\%) & Indexed LAA Ostium Area
(cm\textsuperscript{2}/m\textsuperscript{2}) & 1.67 +/-
0.56\tabularnewline
HFpEF (\% of total) & 7 (6.9\%) & &\tabularnewline
LVEF (\%) & 48.85 +/- 12.5 & &\tabularnewline
HTN (\% of total) & 47 (46.5\%) & LAA Ostial Major Axis Length (cm) &
2.44 +/- 0.48\tabularnewline
DM (\% of total) & 12 (11.9\%) & LAA Ostial Minor Axis Length (cm) &
1.72 +/- 0.34\tabularnewline
Stroke/SSE (\% of total) & 8 (7.9\%) & LAA Ostial Perimeter (cm) & 6.35
+/-1.17\tabularnewline
Smoking (\% of total) & 22 (21.8\%) & LAA Morphology Type
&\tabularnewline
& & Chicken Wing (\% of total) & 78 (77.2\%)\tabularnewline
& & Cauliflower (\% of total) & 10 (9.9\%)\tabularnewline
& & Windsock (\% of total) & 7 (6.93\%)\tabularnewline
& & Cactus (\% of total) & 6 (5.94\%)\tabularnewline
Hx of Cardioversion (\% of total) & 34 (33.7\%) & Failed Trial of
Antiarrhythmics (\% of total) & 39 (38.6\%)\tabularnewline
\bottomrule
\end{longtable}

\emph{Table 1:} Baseline Characteristics of the Study Population.\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& N & LAA Ostium Area (mm\textsuperscript{2}) & p-value & Indexed LAA
Ostium Area (mm\textsuperscript{2}/m\textsuperscript{2}) &
p-value\tabularnewline
\midrule
\endhead
\textbf{HFrEF} & 24 & 388 \selectlanguage{ngerman}± 110.85 & \textbf{0.0148} & 189.67 \selectlanguage{ngerman}± 56.65 &
\textbf{0.0268}\tabularnewline
No HFrEF & 77 & 319.83 \selectlanguage{ngerman}± 115.44 & & 160.22 \selectlanguage{ngerman}± 189.67 &\tabularnewline
\textbf{HTN} & 47 & 347.19 \selectlanguage{ngerman}± 115.79 & 0.2664 & 167.85 \selectlanguage{ngerman}± 60.58 &
1\tabularnewline
No HTN & 54 & 322.67 \selectlanguage{ngerman}± 118.57 & & 166.26 \selectlanguage{ngerman}± 51.58 &\tabularnewline
\textbf{DM} & 12 & 363.75 \selectlanguage{ngerman}± 129.85 & 0.3843 & 175.79 \selectlanguage{ngerman}± 63.6 &
0.6152\tabularnewline
No DM & 89 & 330.23 \selectlanguage{ngerman}± 115.71 & & 165.75 \selectlanguage{ngerman}± 55.25 &\tabularnewline
\textbf{Stroke/SSE} & 8 & 353 \selectlanguage{ngerman}± 207.97 & 0.5561 & 174.33 \selectlanguage{ngerman}± 92.74 &
0.6360\tabularnewline
No Stroke/SSE & 93 & 332.65 \selectlanguage{ngerman}± 107.64 & & 166.38 \selectlanguage{ngerman}± 52.11 &\tabularnewline
\bottomrule
\end{longtable}

\emph{Table 2} : Correlation of LAA Ostium Area and Preexisting
Comorbidities/Risk Factors.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& Correlation & p-value\tabularnewline
\midrule
\endhead
LAA Ostium Area (mm\textsuperscript{2}) with Fibrosis & 0.06226 &
0.5383\tabularnewline
Indexed LAA Ostium Area (mm\textsuperscript{2}/m\textsuperscript{2})
with Fibrosis & 0.02149 & 0.8407\tabularnewline
LAA Ostium Area (mm\textsuperscript{2}) with LA Volume & 0.31034 &
\textbf{0.0017}\tabularnewline
Indexed LAA Ostium Area (mm\textsuperscript{2}/m\textsuperscript{2})
with LA Volume & 0.25668 & \textbf{0.0146}\tabularnewline
LAA Ostium Area (mm\textsuperscript{2}) with Sphericity & 0.02697 &
0.79\tabularnewline
Indexed LAA Ostium Area (mm\textsuperscript{2}/m\textsuperscript{2})
with Sphericity & -0.00345 & 0.9743\tabularnewline
LAA Ostium Area (mm\textsuperscript{2}) with LAA Volume & 0.42015 &
\textbf{\textless{}0.0001}\tabularnewline
Indexed LAA Ostium Area (mm\textsuperscript{2}/m\textsuperscript{2})
with LAA Volume & 0.37534 & \textbf{0.0007}\tabularnewline
LAA Ostium Area (mm\textsuperscript{2}) with LAVI & 0.10935 &
0.2813\tabularnewline
Indexed LAA Ostium Area (mm\textsuperscript{2}/m\textsuperscript{2})
with LAVI & 0.14194 & 0.182\tabularnewline
\bottomrule
\end{longtable}

\emph{Table 3A} : Correlation of LAA Ostial Parameters with LA and LAA
Structural Markers\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
LAA Morphology Type & LAA Ostium Area (mm\textsuperscript{2}) & p-value
& Indexed LAA Ostium Area (mm\textsuperscript{2}/m\textsuperscript{2}) &
p-value\tabularnewline
\midrule
\endhead
Chicken Wing & 340.27 +/- 109.75 & \textbf{0.0111} & 167.71 +/- 50.81 &
\textbf{0.0189}\tabularnewline
Cauliflower & 433.88 +/- 138.97 & & 224.35 +/- 70.86 &\tabularnewline
Windsock & 234.5 +/- 69.19 & & 109.28 +/- 21.41 &\tabularnewline
Cactus & 322.33 +/- 126.79 & & 171.46 +/- 66.04 &\tabularnewline
\bottomrule
\end{longtable}

\emph{Table 3B} : Correlation of LAA Ostial Parameters with LAA
Morphology Type

\textbackslash{}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& Correlation & p-value\tabularnewline
\midrule
\endhead
LAA Ostium Area (mm\textsuperscript{2}) with LAEF & -0.23779 &
\textbf{0.0172}\tabularnewline
Indexed LAA Ostium Area (mm\textsuperscript{2}/m\textsuperscript{2})
with LAEF & -0.28898 & \textbf{0.0057}\tabularnewline
LAA Ostium Area (mm\textsuperscript{2}) with LA Strain (Total) &
-0.18042 & 0.0724\tabularnewline
Indexed LAA Ostium Area (mm\textsuperscript{2}/m\textsuperscript{2})
with LA Strain (Total) & -0.24795 & \textbf{0.0185}\tabularnewline
LAA Ostium Area (mm\textsuperscript{2}) with LA Strain (Passive) &
-0.20025 & \textbf{0.0458}\tabularnewline
Indexed LAA Ostium Area (mm\textsuperscript{2}/m\textsuperscript{2})
with LA Strain (Passive) & 0.2081 & \textbf{0.049}\tabularnewline
LAA Ostium Area (mm\textsuperscript{2}) with LA Strain (Active) &
-0.17137 & 0.0882\tabularnewline
Indexed LAA Ostium Area (mm\textsuperscript{2}/m\textsuperscript{2})
with LA Strain (Active) & -0.19606 & 0.064\tabularnewline
\bottomrule
\end{longtable}

\emph{Table 4:} Correlation of LAA Ostial Parameters with LA Functional
Markers\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Parameter (N=37) & Pre-Ablation & Post-Ablation & p-value\tabularnewline
\midrule
\endhead
LAA Ostium Area (mm\textsuperscript{2}) & 383.89+/- 114.84 & 342.35+/-
95.71 & \textbf{0.0004}\tabularnewline
LVEF (\%) & 48.26 +/- 9.02 & 53.62 +/- 8.82 &
\textbf{0.015}\tabularnewline
LAA Ostium Minor Axis Length (cm) & 19.17 +/- 3.24 & 17.71 +/- 3.03 &
\textbf{0.0004}\tabularnewline
LAVI (mL/m\textsuperscript{2}) & 85.36 +/- 19.55 & 73.67 +/- 12.05 &
0.2204\tabularnewline
LAA Volume (mL) & 8.21 +/- 5.32 & 7.82 +/- 4.01 & 0.9483\tabularnewline
LAEF Total (\%) & 25.82 +/- 14.06 & 25.96 +/- 8.18 &
0.9191\tabularnewline
LA Fibrosis (\%) & 18.45 +/- 6.24 & 13.71 +/- 6.75 &
0.0783\tabularnewline
LA Strain Total (s\textsuperscript{-1}) & 9.51 +/- 4.53 & 8.19 +/- 2.54
& 0.4584\tabularnewline
\bottomrule
\end{longtable}

\emph{Table 5:} Post-Ablation Changes in LA and LAA Morphological and
Functional Parameters.

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