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\begin{document}

\title{Left Atrial Appendage Structural Characteristics Predict Thrombus
Formation}



\author[1]{Carson Castellani}%
\author[2]{Yan Gao}%
\author[3]{Hyun Kim}%
\author[4]{Colton Thompson}%
\author[1]{John Ning}%
\author[5]{Nicole Lohr}%
\author[1]{AIMEE WELSH}%
\author[1]{MARCIE BERGER}%
\affil[1]{Medical College of Wisconsin}%
\affil[2]{Medical College of Wisconsin Division of Biostatistics}%
\affil[3]{Kaiser Permanente Center for Health Research}%
\affil[4]{University of Wisconsin-Madison}%
\affil[5]{UAB Hospital}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Non-valvular atrial fibrillation (NVAF) is a highly
prevalent arrhythmia where loss of synchronized atrial contraction
increases the risk of intracardiac thrombus particularly within the left
atrial appendage (LAA). Anticoagulation is the mainstay of stroke
prevention based on the CHA2DS2-VASc score; however, it does not account
for LAA structural characteristics. \textbf{Methods:} The research
comprises a retrospective matched case-control study of 196 subjects
with NVAF who underwent transesophageal echo (TEE). The control group,
without thrombus (n=117), was selected from two different groups, both
pools had: NVAF and CHA2DS2-VASc score [?] 3. One group underwent
screening TEE prior to Watchman closure device placement from January
2015 to December 2019 (n=74) the second underwent TEE prior to
cardioversion from February to October 2014 (n=43). The study group,
with thrombus (n=79), included patients with NVAF, TEE study performed
between February 2014 and December 2020, and LAA thrombus. The
propensity score method was utilized to determine the matched controls
while accounting for confounding from prognostic variables resulting in
61 matched pairs included in the analysis data set. LAA ostial area (OA)
(calculated from orthogonal measurements 0, 90\selectlanguage{ngerman}° or 45, 135°), LAA
maximal depth, and peak LAA outflow velocity were measured.
\textbf{Results:} Patient characteristics and TEE data were collected
(Table {[}I{]}(\#tbl-cap-0001)) and compared using the t-test or
chi-square analysis. We observed a lower LAA peak exit velocity in the
thrombus group as compared to the control group. Additionally, we found
that patients in the thrombus group had smaller LAA OA at 0 and 90
degrees, at 45 and 135 degrees, using largest diameter, as well as using
aggregate OA, and smaller maximum LAA depth compared to patients in the
control group. Candidate conditional logistic regression models for the
outcome of presence of thrombus were evaluated (Table
{[}II{]}(\#tbl-cap-0002)). Statistical results from the best-fitting
conditional regression model were calculated (Table
{[}III{]}(\#tbl-cap-0003)) showing a significant association between
aggregate OA and LAA exit velocity with presence of thrombus.
\textbf{Conclusion:} Utilizing LAA structural characteristics to predict
thrombus formation may help refine current cardioembolic stroke (CES)
risk estimation.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Title:}

Left Atrial Appendage Structural Characteristics Predict Thrombus
Formation

\textbf{Short title} :

LAA Characteristics Predict Thrombus Formation

\textbf{Authors:}

Carson Castellani, MD, MPH\textsuperscript{a}

Ccastellani@mcw.edu

Yan Gao, PhD\textsuperscript{b}

Yagao@mcw.edu

Hyun Kim, DO\textsuperscript{c}

Hyun.j3.kim@kp.org

Colton Thompson, MD\textsuperscript{d}

Cthompson9@uwhealth.org

John Ning, MD\textsuperscript{a}

Jning@mcw.edu

Nicole Lohr, MD, PhD, FACC\textsuperscript{e}

Nicole.lohr@va.gov

Aimee Welsh, MD, FACC\textsuperscript{a}

Awelsh@mcw.edu

Marcie Berger, MD, FACC\textsuperscript{a}

mgberger@mcw.edu

Affiliated addresses:

\textsuperscript{a} Medical College of Wisconsin Affiliated Hospitals

8701 Watertown Plank Rd.

Milwaukee, WI USA 53226

\textsuperscript{b} Division of Biostatistics,

Medical College of Wisconsin

8701 Watertown Plank Rd.

Milwaukee, WI USA 53226

\textsuperscript{c} Kaiser Permanente Building

500 NE. Multnomah St. \#100

Portland, OR USA 97232

\textsuperscript{d} University of Wisconsin Hospital

600 Highland Ave.

Madison, WI USA 53792

\textsuperscript{e} University of Alabama Birmingham

2000 6\textsuperscript{th} Ave. S.

Birmingham, AL USA 35294

\textbf{Corresponding author:}

Marcie Berger, MD, FACC

mgberger@mcw.edu

Medical College of Wisconsin Affiliated Hospitals

8701 Watertown Plank Rd.

Milwaukee, WI USA 53226

Business phone 414-955-6861 Fax 414-955-0069

\textbf{Declarations of interest:} none

\textbf{Keywords:}

atrial fibrillation; left atrial appendage thrombus; left atrial
appendage anatomy

\textbf{Abstract:}

\textbf{Background:} Non-valvular atrial fibrillation (NVAF) is a highly
prevalent arrhythmia where loss of synchronized atrial contraction
increases the risk of intracardiac thrombus particularly within the left
atrial appendage (LAA). Anticoagulation is the mainstay of stroke
prevention based on the CHA2DS2-VASc score; however, it does not account
for LAA structural characteristics.

\textbf{Methods:} The research comprises a retrospective matched
case-control study of 196 subjects with NVAF who underwent
transesophageal echo (TEE). The control group, without thrombus (n=117),
was selected from two different groups, both pools had: NVAF and
CHA2DS2-VASc score [?] 3. One group underwent screening TEE prior to
Watchman closure device placement from January 2015 to December 2019
(n=74) the second underwent TEE prior to cardioversion from February to
October 2014 (n=43). The study group, with thrombus (n=79), included
patients with NVAF, TEE study performed between February 2014 and
December 2020, and LAA thrombus. The propensity score method was
utilized to determine the matched controls while accounting for
confounding from prognostic variables resulting in 61 matched pairs
included in the analysis data set. LAA ostial area (OA) (calculated from
orthogonal measurements 0, 90\selectlanguage{ngerman}° or 45, 135°), LAA maximal depth, and peak
LAA outflow velocity were measured.

\textbf{Results:} Patient characteristics and TEE data were collected
(Table I) and compared using the t-test or chi-square analysis. We
observed a lower LAA peak exit velocity in the thrombus group as
compared to the control group. Additionally, we found that patients in
the thrombus group had smaller LAA OA at 0 and 90 degrees, at 45 and 135
degrees, using largest diameter, as well as using aggregate OA, and
smaller maximum LAA depth compared to patients in the control group.
Candidate conditional logistic regression models for the outcome of
presence of thrombus were evaluated (Table II). Statistical results from
the best-fitting conditional regression model were calculated (Table
III) showing a significant association between aggregate OA and LAA exit
velocity with presence of thrombus.

\textbf{Conclusion:} Utilizing LAA structural characteristics to predict
thrombus formation may help refine current cardioembolic stroke (CES)
risk estimation.

\textbf{Background:~}

In atrial fibrillation (AF), thrombus formation typically occurs within
the left atrial appendage (LAA) and is less common in the left atrial
cavity (LAC)\textsuperscript{1-3}. Based on transesophageal
echocardiography (TEE), the prevalence of LAA thrombus in AF patients in
the absence of anticoagulation is 7.5\%, with a 1.8\% prevalence of LAC
thrombus\textsuperscript{4}, though extra-appendage thrombus appears to
be a rare finding in non-valvular atrial
fibrillation\textsuperscript{5}. LAA/LAC thrombus may be associated with
embolization to the brain, causing stroke. The LAA has distinct
structural, anatomic, and physiologic properties that permit the
structure to serve its role as a decompression chamber during periods of
elevated left atrial pressure. The volume, orifice size, length, shape,
and lobulation of the LAA may vary markedly between
individual\textsuperscript{6, 7}.

The pathogenesis of thrombus formation in the LAA in the setting of
non-valvular AF (NVAF) is not fully understood. Investigators have
examined structural and functional characteristics of the LAA and how
they contribute to LAA thrombus formation and cardioembolic stroke (CES)
risk. Reduced blood inflow and outflow velocities at the LAA orifice
based upon Doppler transesophageal echocardiography (TEE) measurements
have predicted LAA thrombus risk\textsuperscript{8}. More recent studies
seeking to correlate descriptive LAA morphologies with thromboembolic
risk have reported lower risks of embolic events with Chicken-Wing LAA
morphology\textsuperscript{7-9}.

The LAA anatomic determinants that predict thromboembolic risk in NVAF
have not been completely elucidated. This study aimed to compare the LAA
orifice size, maximal depth, and peak~exit~velocities between AF
patients with LAA thrombus and high-risk AF patients without thrombus.
Identifying novel LAA anatomic determinants of thrombus formation may
help stratify AF thromboembolic risk in the future.

\textbf{Methods:~}

\emph{Study design and patient population.}

The study procedures were reviewed and approved by the Institutional
Research Board (IRB) of Medical College of Wisconsin. In this
single-center retrospective study, AF patients with LAA thrombus were
identified through a query of ICD-10 codes within the electronic medical
record system. This search identified patients with the diagnosis of
non-valvular atrial fibrillation (NVAF), a TEE study performed between
February 1, 2014, and December 31, 2020, and a diagnosis of intracardiac
thrombus. In this manner 216 subjects were identified. Two study
cardiologists (MB and AW) manually reviewed the TEE images and medical
records for these subjects. Subjects with intracardiac thrombus not
contained within the LAA or thrombus unconfirmed by the two study
reviewers, and those for whom imaging did not permit orthogonal
measurements of the left atrial appendage ostial diameters were excluded
from the study. A total of 79 patients constituted the final thrombus
cohort (Figure 1).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1. Flow chart depicting patient selection methodology.

The control cohort for this study was identified differently. The
control group included consecutive patients identified with the
following characteristics: a
CHA\textsubscript{2}DS\textsubscript{2}-VASc score of 3 or more,
documentation of NVAF, underwent screening TEE before Watchman LAA
closure device (Boston Scientific Corporation, St Paul MN) placement
from January 1, 2015, to December 31, 2019, and absence of LAA thrombus
on screening TEE. A total of 74 subjects were thus identified and
included in the control cohort. The control group was selected based on
prior Watchman screening for their elevated risk for LAA thrombus based
on an elevated CHA\textsubscript{2}DS\textsubscript{2}-VASc score, the
presence of prior TEE imaging, confirmed absence of LAA thrombus on TEE,
and prior confirmed history of AF. Additional subjects were added to the
control cohort with the following characteristics: CHA2DS2-VASc score of
3 or more, documentation of NVAF, underwent TEE prior to cardioversion
from February to October 2014, and absence of LAA thrombus on TEE. A
total of 43 subjects were thus identified and included in the control
cohort resulting in 117 total subjects (Figure 1). For all 117 control
subjects, imaging permitted orthogonal measurements of the LAA ostial
diameters. Primary TEE imaging and electronic medical record data were
confirmed by two study cardiologists (MB and AW).

\emph{Transesophageal echocardiography and measurement of clinical
parameters} .

2D multiplane TEE was performed and interpreted by experienced
cardiologists using an EPIQ ultrasound system and X8-2t probe (Philips
Medical Systems, Andover, MA). Studies were performed according to the
American Society of Echocardiography guidelines. LAA peak exit
velocities were measured approximately 1 cm below the outlet of the LAA
cavity using pulse wave Doppler ultrasound in the 45\selectlanguage{ngerman}°~view. Peak exit
velocities were measured as the average of three consecutive cardiac
cycles in patients with normal sinus rhythm and five consecutive cardiac
cycles in patients with AF at the time of examination. The LAA imaging
was obtained at end-diastole when the LAA diameter and volume was
maximal; and was evaluated in four different mid-esophageal planes: 0°,
45°, 90°, and 135°. In each of the four planes, LAA ostial diameters
were measured from the inferior portion of the ostium at the level of
the circumflex coronary artery up to the point 2 cm from the tip of the
left superior pulmonary vein limbus. In each plane, LAA depth was
measured from the ostial line orthogonal to the LAA neck axis to the LAA
apex. Given the retrospective nature of the study, measurements at all
four mid-esophageal planes were not uniformly available. All TEE studies
were independently reviewed by two cardiologists. The final LAA ostial
diameter and length measurements were derived from an average of the
echocardiographers' measurements. The orifice area was calculated using
two orthogonal measured ostial radiuses (\emph{a} ) and (\emph{b} )
using the formula~\selectlanguage{greek}\emph{πab}\selectlanguage{english} . Orthogonal LAA radiuses were measured at
TEE planes 0\selectlanguage{ngerman}° and 90°, as well as 45°and 135°, provided all four planes
were available for review. Aggregate OA was calculated as the average of
the measured OAs for the subjects where all four mid-esophageal planes
were available (0° and 90°, as well as 45°and 135°). In the case that
only one pair of orthogonal measurements (0° and 90° or 45°and 135°) was
available then this value alone was used in the calculation of aggregate
OA. Similarly, regarding OA at the largest diameter, when all four
mid-esophageal planes were available (0° and 90°, as well as 45°and
135°) the largest diameter and its orthogonal plane was selected. 42 of
the 61 subjects in the thrombus group and 48 of the 61 subjects in the
control group had all four mid-esophageal planes available. LAA thrombus
was identified as independently mobile echo-densities that corresponded
with contrast echocardiography filling defects.

Chart review was completed for each patient to determine anticoagulation
status, underlying rhythm, and CHA2DS2-VASc score all at the time of
TEE. Medical history was also reviewed for ischemic stroke or TIA
history.

\emph{Statistical Analysis}

In this matched case-control study, the exposures consist of two
clusters of variables. The first cluster includes 4 variables associated
with the ostial area: OA at 0 and 90 degrees, OA at 45 and 135 degrees,
OA calculated using the largest radius in the 4 TEE planes and the
orthogonal radius, and aggregate OA. The other cluster includes two
variables: Maximum LAA depth and LAA Exit Velocity. The outcome is a
binary variable called LAA thrombus (Yes vs. No). The patients with
thrombus were identified as cases. The patients without thrombus were
considered as the candidate controls. The propensity score method was
utilized to determine the matched controls while accounting for
confounding from prognostic variables. The matching variables included
age, LVEF, and sinus rhythm at the time of TEE. The greedy nearest
neighbor technique was used to achieve the 1:1 matched design to produce
the slightest within-pair difference. Patients were matched only if the
difference in the logits of the propensity scores for pairs of patients
were less than or equal to 0.5 times the pooled estimate of the standard
deviation (see Figure 2). Another variable, therapeutic anticoagulation
at the time of TEE, was exactly matched. Thus, the possibility of
investigating the independent effects of those variables on the outcome
can be effectively eliminated. 61 matched pairs were identified in the
analysis data set (Figure 1).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2. Propensity score matching plot.

Continuous variables were summarized using descriptive statistics such
as mean and standard error. All categorical variables were summarized
using frequencies and percentages. To further investigate the balance of
prognostic variables between the case and control groups, univariate
analyses were performed using the t-test or chi-square test upon
specific requirements. All the variables associated with prognostic
factors and disease history demonstrated no significant impact on the
outcome, except one variable, LVEF (see Table I). The conditional
logistic regressions (an extension of logistic regression which
considers stratification and matching) were used to examine the
potential association between the exposure(s) and the outcome while
adjusting for the covariate LVEF. A unique matching ID for each pair was
generated to indicate the stratum. Thus, the matched variables were
controlled simultaneously because their combined information was already
incorporated into the matched pairs by this ID. To identify the
best-fitting model, we conducted a model selection process based on 6
candidate models whose exposure variables varied (see Table II). The
goodness-of-fit measurement Akaike information criterion (AIC) was used
to compare these candidates. The preferred model is the one with the
minimum AIC value. Thus, Model 1 was the final model for our statistical
results and inference. Odds ratios and 95\% confidence intervals were
reported in Table III and displayed in the forest plot (Figure 3). All
analyses were performed at a two-sided 5\% Type I error rate by SAS 9.4
(SAS Institute, Cary, NC).



\textbf{Results:~}

Table I summarizes the patient characteristics and TEE data for the
control cohort and the thrombus cohort for the 61 matched pairs.
Univariate analysis showed a significant difference (p = 0.0285) between
the cohorts in LVEF with the control group (50.4\% \selectlanguage{ngerman}± 1.5) having greater
left ventricular systolic function compared to the thrombus group
(45.1\% ± 1.8). There were no significant differences between the
thrombus and control cohorts in age at TEE (69.1 ± 1.7 vs 71.0 ± 1.4 p =
0.3885), sex (p = 0.2694), BMI (30.2 ± 1.1 vs 32.9 ± 1.1 p = 0.0784),
pulmonary artery systolic pressure (37.9 ± 1.7 vs 38.3 ± 1.7 p =
0.8529), CHA2DS2-VASc Score (4.5 ± 0.3 vs 4.1 ± 0.2 p = 0.2485), rates
of hypertension (95.1\% vs 91.8\% p = 0.4645), diabetes (39.3\% vs
27.9\% p = 0.1797), stroke, TIA, or thromboembolism (26.2\% vs 24.6\% p
= 0.8353), peripheral arterial disease (31.15\% vs 44.3\% p = 0.1351),
myocardial infarction (24.6\% vs 18.0\% p = 0.3765), coronary artery
disease (55.8\% vs 41.0\% p = 0.1030), LA volume index (50.9 ± 2.1 vs
48.9 ± 1.7 p = 0.4685), therapeutic anticoagulation status at TEE
(98.4\% vs 98.4\% p = 1.0000), or sinus rhythm at TEE (8.20\% vs 8.20\%
p = 1.0000). There were significant differences between the thrombus and
control cohorts in ostial area at 0 and 90 degrees (231.7 ± 13.0 vs
328.6 ± 12.9 p \textless{}0.0001), ostial area at 45 and 135 degrees
(229.3 ± 12.6 vs 336.4 ± 14.1 p \textless{}0.0001), ostial area at the
largest diameter (239.0 ± 12.1 vs 356.3 ± 13.5 p \textless{}0.0001),
aggregate ostial area (223.3 ± 11.0 vs 334.2 ± 12.4 p
\textless{}0.0001), maximum LAA depth (26.7 ± 0.7 vs 29.4 ± 0.7 p =
0.0088), and LAA exit velocity (24.7 ± 1.6 vs 37.9 ± 2.6 p
\textless{}0.0001).

Table I. Univariate Analysis of Patient Characteristics and TEE Data\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Thrombus} (N=61)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{No Thrombus} (N=61)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{P Value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Patient Characteristics}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age at TEE (years)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
69.1 \selectlanguage{ngerman}± 1.7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
71.0 \selectlanguage{ngerman}± 1.4\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.3885\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sex (Male/Female)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
39/22\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
33/28\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.2694\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BMI (kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
30.2 \selectlanguage{ngerman}± 1.1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
32.9 \selectlanguage{ngerman}± 1.1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.0784\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Pulmonary systolic pressure (mmHg)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
37.9 \selectlanguage{ngerman}± 1.7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
38.3 \selectlanguage{ngerman}± 1.7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.8529\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
LVEF (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
45.1 \selectlanguage{ngerman}± 1.8\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
50.4 \selectlanguage{ngerman}± 1.5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.0285\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CHA2DS2-VASc Score\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4.5 \selectlanguage{ngerman}± 0.3\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4.1 \selectlanguage{ngerman}± 0.2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.2485\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hypertension (total, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
58 (95.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
56 (91.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.4645\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Diabetes (total, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
24 (39.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
17 (27.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.1797\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Stroke, TIA, Thromboembolism (total, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16 (26.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15 (24.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.8353\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Peripheral Arterial Disease (total, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19 (31.15)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
27 (44.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.1351\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Myocardial Infarction (total, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15 (24.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11 (18.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.3765\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Coronary artery disease (total, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
34 (55.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
25 (41.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.1030\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{TEE Data}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
LA Volume Index (mL/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
50.9 \selectlanguage{ngerman}± 2.1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
48.9 \selectlanguage{ngerman}± 1.7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.4685\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Anticoagulated at TEE (total, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
60 (98.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
60 (98.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.0000\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sinus Rhythm at TEE (total, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (8.20)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (8.20)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.0000\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
OA at 0 and 90 degrees (mm\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
231.7 \selectlanguage{ngerman}± 13.0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
328.6 \selectlanguage{ngerman}± 12.9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.0001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
OA at 45 and 135 degrees (mm\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
229.3 \selectlanguage{ngerman}± 12.6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
336.4 \selectlanguage{ngerman}± 14.1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.0001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
OA at the largest diameter (mm\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
239.0 \selectlanguage{ngerman}± 12.1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
356.3 \selectlanguage{ngerman}± 13.5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.0001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aggregate OA* (mm\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
223.3 \selectlanguage{ngerman}± 11.0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
334.2 \selectlanguage{ngerman}± 12.4\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.0001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maximum LAA depth (mm)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
26.7 \selectlanguage{ngerman}± 0.7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
29.4 \selectlanguage{ngerman}± 0.7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.0088\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
LAA Exit Velocity (cm/sec)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
24.7 \selectlanguage{ngerman}± 1.6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
37.9 \selectlanguage{ngerman}± 2.6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.0001\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

* Aggregate OA was calculated as the average of the measured OAs for the
subjects where all four mid-esophageal planes were available (0\selectlanguage{ngerman}° and
90°, as well as 45°and 135°). In the case that only one pair of
orthogonal measurements (0° and 90° or 45°and 135°) then the available
value was used. 42 of the 61 subjects in the thrombus group and 48 of
the 61 subjects in the control group had all four mid-esophageal planes
available.

\selectlanguage{english}+ TEE = transesophageal echo, BMI = body mass index, LVEF = left
ventricular ejection fraction, TIA = transient ischemic attack, LA =
left atrial, OA = ostial area, LAA = left atrial appendage

Table II summarizes candidate conditional logistical regression models
for the outcome presence of LAA thrombus. Model 1 included aggregate OA,
LAA exit velocity, and LVEF and was selected as the final model for
statistical results and inference based on the lowest AIC (27.578)
representing the best goodness-of-fit measurement among the candidate
models. Table III summarizes results from the best-fitting conditional
regression model (Model 1) examining the relationship of aggregate OA,
LAA exit velocity, and LVEF to the primary outcome presence of thrombus.
There was a significant association found between aggregate OA and
presence of LAA thrombus (p = 0.0038) as well as LAA exit velocity and
presence of LAA thrombus (p=0.0107) in the logistic regression model,
supporting these two LAA characteristics as risk factors for presence of
LAA thrombus. There was no association (p = 0.2161) between LVEF and
presence of LAA thrombus in the logistic regression analysis, suggesting
that LVEF does not represent an independent risk factor predictive of
LAA thrombus. These results are depicted graphically in Figure 3, a
Forest plot for the best-fitting conditional logistic regression.

Table II. Candidate Conditional Logistic Regression Models for the
Outcome (Thrombus or not)\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
& \textbf{Model 1} & \textbf{Model 2} & \textbf{Model 3} & \textbf{Model
4} & \textbf{Model 5} & \textbf{Model 6}\tabularnewline
\midrule
\endhead
\textbf{Strata identified by Matched ID} & X & X & X & X & X &
X\tabularnewline
\textbf{Exposure variables *} & & & & & &\tabularnewline
Aggregate OA & X & X & & & &\tabularnewline
LAA Exit Velocity & X & & X & & &\tabularnewline
OA at the largest diameter & & & & X & &\tabularnewline
OA at 45 and 135 degrees & & & & & X &\tabularnewline
Maximum LAA depth & & & & & & X\tabularnewline
\textbf{Prognostic factor} & & & & & &\tabularnewline
LVEF & X & X & X & X & X & X\tabularnewline
\textbf{Modeling Fitting measurement} & & & & & &\tabularnewline
AIC & 27.578 & 43.303 & 50.859 & 44.868 & 45.197 & 66.146\tabularnewline
\bottomrule
\end{longtable}

* OA at 0 and 90 degrees were not considered due to more than 20\%
missing data (i.e., 26 patients out of 122).

+ OA = ostial area, LAA = left atrial appendage, LVEF = left ventricular
ejection fraction, AIC = Akaike information criterion

Table III. Statistical results from the best-fitting conditional
regression model (Model 1)\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Predictor variables} & \textbf{Estimate (SE)} & \textbf{OR
(95\%CI)} & \textbf{P Value}\tabularnewline
\midrule
\endhead
Aggregate OA & -0.0208 (0.0072) & 0.979 (0.966, 0.993) &
0.0038\tabularnewline
LAA exit velocity & -0.1065 (0.0417) & 0.899 (0.828, 0.976) &
0.0107\tabularnewline
LVEF & -0.0763(0.0617) & 0.927 (0.821, 1.046) & 0.2161\tabularnewline
\bottomrule
\end{longtable}

*SE = standard error, OR = odds ratio, CI = confidence interval, OA =
ostial area, LAA = left atrial appendage, LVEF = left ventricular
ejection fraction\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure 3. Forest plot for the best-fitting conditional logistic
regression.

\textbf{Discussion:}

Widely used scores predicting CES risk in NVAF have emphasized clinical
characteristics including age and comorbidities. Few studies have
explored the contribution of LAA structural characteristics to
thrombotic risk. Clarifying the relationships between LAA anatomy,
physiology, and thrombotic risk may refine CES risk estimates and impact
anticoagulation or other stroke mitigation procedure decisions for NVAF
patients.

Previous examinations of LAA morphologic determinants of CES risk relied
on qualitative classifications of LAA shape, distinguishing between
appendages that resemble a Chicken-Wing, Windsock, Cactus, and
Cauliflower\textsuperscript{7}. Several studies have demonstrated a
lower risk of stroke and transient ischemic attack, and a higher LAA
emptying flow velocities with Chicken-Wing type LAAs compared to other
LAA morphologic types\textsuperscript{7-9}. The variable appearance of
LAA morphology in different TEE imaging planes, as well as LAA anatomic
complexity and heterogeneity, may limit the reproducibility and utility
of such morphologic criteria. Wu et al. examined inter-observer
agreements categorizing qualitative descriptions of LAA morphology by CT
in 2264 AF patients and found that all 3 reviewers came to consensus in
only 28.9\% of scans\textsuperscript{10}. Thus, LAA anatomic and
physiologic measurements that are objective and reproducible could be
valuable in predicting thrombus formation and thromboembolic risk in
NVAF.

Lower LAA emptying velocities are known to confer higher risk of
thrombogenesis\textsuperscript{8}. The presence of AF during TEE and
persistent AF has predicted lower maximal LAA emptying flow velocities.
Petersen et al. observed higher flow velocities in patients with AF who
had Chicken-Wing LAA morphology, but interestingly only when patients
were in sinus rhythm at the time of TEE\textsuperscript{11}. After
controlling for sinus rhythm at the time of TEE, we observed lower LAA
exit velocities in the LAA thrombus cohort, consistent with prior
publications.

The relationship between the LAA orifice area, a simple and reproducible
measurement on TEE and cardiac CT, and thromboembolic risk in NVAF is
unclear as previously published findings are conflicting. Khurram et al.
studied 678 patients undergoing AF ablation with pre-procedure cardiac
CT imaging, reporting an association of smaller LAA orifice size with
thromboembolic events in univariate analyses\textsuperscript{12}. In
contrast, Lee JM et al. found that NVAF patients with stroke had larger
LAA orifice area and larger LA volume\textsuperscript{13}. Similarly,
Lee Y et al. demonstrated larger LAA orifice diameters in patients with
CES\textsuperscript{14}. These conflicting reports describing the
relationship of LAA orifice size and CES risk highlight the importance
of further investigation.

In contrast to prior work examining the relationship between LAA
structural characteristics and clinical thromboembolic event risk in AF,
our study examines the structure and function of the LAA in AF patients
with documented LAA thrombus. This difference in outcome of interest
compared to previous studies that used clinical history of stroke and
TIA as a surrogate for intracardiac thrombus formation represents a
unique aspect of our study insulating our results from the variability
associated with accurately diagnosing stroke or TIA. While most ischemic
strokes in patients with NVAF are cardioembolic, at least 24\% may have
a non-cardioembolic etiology\textsuperscript{15}. It may therefore be
advantageous to directly study patients with documented LAA thrombus
when characterizing LAA measurements that potentially predict thrombus
formation in NVAF. We observed a lower LAA peak exit velocity in the
thrombus group as compared to the control group (24.7 \selectlanguage{ngerman}± 1.6 cm/s vs.
37.9 ± 2.6 cm/s, p \textless{}0.0001). Additionally, we found that
patients in the thrombus group had smaller LAA OA at 0 and 90 degrees
(231.7 ± 13.0 mm\textsuperscript{2} vs. 328.6 ± 12.9
mm\textsuperscript{2}, p\textless{}0.001), smaller LAA OA at 45 and 135
degrees (229.3 ± 12.6 mm\textsuperscript{2} vs. 336.4 ± 14.1
mm\textsuperscript{2}, p\textless{}0.0001), smaller OA at the largest
diameter (239.0 ± 12.1 mm\textsuperscript{2} vs. 356.3 ± 13.5
mm\textsuperscript{2}, p\textless{}0.0001), smaller aggregate OA (223.3
± 11.0 mm\textsuperscript{2} vs. 334.2 ± 12.4 mm\textsuperscript{2},
p\textless{}0.0001), and smaller maximum LAA depth (26.7 ± 0.7 mm vs.
29.4 ± 0.7 mm, p=0.0088) as compared to patients in the control group.
Our primary novel finding, smaller LAA ostial area as an independent
risk factor for LAA thrombus in NVAF, may help refine current CES risk
estimation models. In particular, incorporating physiologic and anatomic
measurements in clinical thromboembolic risk models may be useful to
identify truly low-risk AF patients.

There were several limitations to this study. In this case-control
study, we identified patients with NVAF that were placed into the
thrombus and control groups from different populations of NVAF patients
undergoing TEE. This permitted identification of a larger number of
patients for the thrombus group but introduced selection bias into the
study. We undertook propensity matching in order to reduce the
possibility of confounding from differences in baseline characteristics
between the groups including age, LVEF, anticoagulation status at time
of TEE, and sinus rhythm at time of TEE. Despite the propensity
matching, a significant difference in the baseline characteristic of
LVEF persisted with the thrombus group having a lower LVEF compared to
the control group (45.1 ± 1.8\% vs. 50.4 ± 1.5\%, p=0.0285). However,
this association did not persist after best-fitting conditional
regression model analysis was performed (p=0.2161). Given the
retrospective identification of patients, LAA ostial diameter
measurements via TEE at all four mid-esophageal planes (0° and 90°, as
well as 45°and 135°) were not universally available. Aggregate OA was
calculated in order to incorporate maximal available measured LAA ostial
data. Aggregate OA was found to be significantly smaller in the thrombus
cohort as were all other OA evaluations including OA at 0° and 90°, OA
at 45°and 135° and OA at largest diameter adding validity to these
significant findings. Finally, the calculation of the OA used an ellipse
formula that does not factor in the irregular shape of the LAA ostium.
This limitation likely has less significance as both groups were
evaluated with the same formulaic assumptions.

\textbf{Conclusion:~}

Our study identified smaller LAA ostial cross-sectional area as a novel
predictor of LAA thrombus risk, independent of LAA peak exit velocity.
Incorporating structural and physiologic LAA measurements into clinical
thromboembolic risk stratification may improve decisions regarding risk
mitigation in NVAF.

\textbf{Citations:}

1. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in
cardiac surgical patients with atrial fibrillation. Ann Thorac Surg. Feb
1996;61(2):755-9. doi:10.1016/0003-4975(95)00887-X

2. Cresti A, García-Fernández MA, Sievert H, et al. Prevalence of
extra-appendage thrombosis in non-valvular atrial fibrillation and
atrial flutter in patients undergoing cardioversion: a large
transoesophageal echo study. EuroIntervention. Jun 2019;15(3):e225-e230.
doi:10.4244/EIJ-D-19-00128

3. Scherr D, Sharma K, Dalal D, et al. Incidence and predictors of
periprocedural cerebrovascular accident in patients undergoing catheter
ablation of atrial fibrillation. J Cardiovasc Electrophysiol. Dec
2009;20(12):1357-63. doi:10.1111/j.1540-8167.2009.01540.x

4. Noubiap JJ, Agbaedeng TA, Ndoadoumgue AL, et al. Atrial thrombus
detection on transoesophageal echocardiography in patients with atrial
fibrillation undergoing cardioversion or catheter ablation: A pooled
analysis of rates and predictors. J Cardiovasc Electrophysiol.
2021;32(8):2179-2188. doi:10.1111/jce.15082, 10.1111/jce.15082

5. Cresti A, Garcia-Fernandez MA, Sievert H, et al. Prevalence of
extra-appendage thrombosis in non-valvular atrial fibrillation and
atrial flutter in patients undergoing cardioversion: a large
transoesophageal echo study. EuroIntervention. 2019;15(3):e225-e230.
doi:10.4244/EIJ-D-19-00128, 10.4244/EIJ-D-19-00128

6. Beigel R, Wunderlich NC, Ho SY, Arsanjani R, Siegel RJ. The left
atrial appendage: anatomy, function, and noninvasive evaluation. JACC
Cardiovasc Imaging. Dec 2014;7(12):1251-65.
doi:10.1016/j.jcmg.2014.08.009

7. Wang Y, Di Biase L, Horton RP, Nguyen T, Morhanty P, Natale A. Left
atrial appendage studied by computed tomography to help planning for
appendage closure device placement. J Cardiovasc Electrophysiol. Sep
2010;21(9):973-82. doi:10.1111/j.1540-8167.2010.01814.x

8. Di Biase L, Santangeli P, Anselmino M, et al. Does the left atrial
appendage morphology correlate with the risk of stroke in patients with
atrial fibrillation? Results from a multicenter study. J Am Coll
Cardiol. Aug 2012;60(6):531-8. doi:10.1016/j.jacc.2012.04.032

9. Basu-Ray I, Sudhakar D, Schwing G, et al. Complex Left Atrial
Appendage Morphology Is an Independent Risk Factor for Cryptogenic
Ischemic Stroke. Front Cardiovasc Med. 2018;5:131.
doi:10.3389/fcvm.2018.00131

10. Wu L, Liang E, Fan S, et al. Relation of Left Atrial Appendage
Morphology Determined by Computed Tomography to Prior Stroke or to
Increased Risk of Stroke in Patients With Atrial Fibrillation. Am J
Cardiol. 04 2019;123(8):1283-1286. doi:10.1016/j.amjcard.2019.01.024

11. Petersen M, Roehrich A, Balzer J, et al. Left atrial appendage
morphology is closely associated with specific echocardiographic flow
pattern in patients with atrial fibrillation. Europace. Apr
2015;17(4):539-45. doi:10.1093/europace/euu347

12. Khurram IM, Dewire J, Mager M, et al. Relationship between left
atrial appendage morphology and stroke in patients with atrial
fibrillation. Heart Rhythm. Dec 2013;10(12):1843-9.
doi:10.1016/j.hrthm.2013.09.065

13. Lee JM, Shim J, Uhm JS, et al. Impact of increased orifice size and
decreased flow velocity of left atrial appendage on stroke in
nonvalvular atrial fibrillation. Am J Cardiol. Mar 2014;113(6):963-9.
doi:10.1016/j.amjcard.2013.11.058

14. Lee Y, Park HC, Kim SG. Comparison of Morphologic Features and Flow
Velocity of the Left Atrial Appendage Among Patients With Atrial
Fibrillation Alone, Transient Ischemic Attack, and Cardioembolic Stroke.
Am J Cardiol. 05 2017;119(10):1596-1604.
doi:10.1016/j.amjcard.2017.02.016

15. Freeman JV, Varosy P, Price MJ, et al. The NCDR Left Atrial
Appendage Occlusion Registry. J Am Coll Cardiol. 04
2020;75(13):1503-1518. doi:10.1016/j.jacc.2019.12.

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\selectlanguage{english}
\FloatBarrier
\end{document}

