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\begin{document}

\title{Left Atrial Strain, Embolic Stroke of Undetermined Source, and Atrial
Fibrillation Detection}



\author[1]{Zubair Bashir}%
\author[1]{Edward W. Chen}%
\author[2]{Shuyuan Wang}%
\author[3]{Liqi Shu}%
\author[3]{Eric D. Goldstein}%
\author[3]{Maheen Rana}%
\author[3]{Narendra Kala}%
\author[3]{Xing Dai}%
\author[3]{Daniel Mandel}%
\author[4]{Phinnara Has}%
\author[2]{Mingxing Xie}%
\author[5]{Tao Wang}%
\author[6]{John Dickey}%
\author[1]{Athena Poppas}%
\author[1]{James Simmons}%
\author[1]{Christopher Song}%
\author[3]{Shadi Yaghi}%
\author[1]{Philip Haines}%
\affil[1]{Brown University Warren Alpert Medical School}%
\affil[2]{Huazhong University of Science and Technology Tongji Medical College}%
\affil[3]{Brown University Department of Neurology}%
\affil[4]{Rhode Island Hospital}%
\affil[5]{Stanford Cardiovascular Institute}%
\affil[6]{University of Massachusetts Chan Medical School Division of Cardiovascular Medicine}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Atrial cardiopathy is a proposed mechanism of
embolic stroke of undetermined source (ESUS). Left atrial (LA) strain
may identify early atrial cardiopathy prior to structural changes. We
aim to study the associations between LA strain, ESUS, and atrial
fibrillation (AF) detection in ESUS. \textbf{Methods:} The study
population included patients with ESUS and non-cardioembolic (NCE)
stroke presenting to statewide stroke center between January 2016 and
June 2017 who underwent transthoracic echocardiography. Speckle tracking
echocardiography (STE) was used to measure the 3 phases of LA strain
(reservoir, conduit, and contractile). Binary logistic regression
analysis was performed to determine the associations between LA strain
and stroke subtype (ESUS vs. NCE) as well as follow-up detection of AF
in ESUS patients. \textbf{Results:} We identified 656 patients, 307 with
ESUS and 349 with NCE. In binary logistic regression, the lowest
tertiles of LA reservoir (adjusted OR 1.944, 95\% CI 1.266-2.986, p =
0.002), contractile (aOR 1.568, 95\% CI 1.035-2.374, p = 0.034), and
conduit strain (aOR 2.288, 95\% CI 1.448-3.613, p = 0.001) were more
likely to be significantly associated with ESUS compared to NCE stroke.
Among all ESUS patients, the lowest tertiles of LA reservoir strain (OR
2.534, 95\% CI 1.029-6.236, p = 0.043), contractile strain (OR 2.828,
95\% CI 1.158-6.903, p = 0.022), and conduit strain (OR 2.614, 95\% CI
1.003-6.815, p = 0.049) were significantly associated with subsequent
detection of AF. \textbf{Conclusion:} Reduced LA strain is associated
with ESUS occurrence and AF detection in ESUS patients. Therefore,
quantification of LA strain in ESUS patients may improve risk
stratification and guide secondary prevention strategies.%
\end{abstract}%



\sloppy


\textbf{Full title:} Left Atrial Strain, Embolic Stroke of Undetermined
Source, and Atrial Fibrillation Detection

\textbf{Short title:} Reduced Left Atrial Strain and ESUS

\textbf{Authors:} Zubair Bashir, MD\textsuperscript{a}; Edward W. Chen,
ScB\textsuperscript{a}; Shuyuan Wang, MD, PhD\textsuperscript{b}; Liqi
Shu, MD\textsuperscript{c}; Eric D. Goldstein, MD\textsuperscript{c};
Maheen Rana, MD\textsuperscript{c}; Narendra Kala,
MD\textsuperscript{c}; Xing Dai, MD\textsuperscript{c}; Daniel Mandel,
MD\textsuperscript{c}; Phinnara Has, MS\textsuperscript{d}; Mingxing
Xie, MD, PhD\textsuperscript{b}; Tao Wang, PhD\textsuperscript{e}; John
B Dickey, MD\textsuperscript{f}; Athena Poppas, MD\textsuperscript{a};
James Simmons, MD\textsuperscript{g}; Christopher Song,
MD\textsuperscript{a}; Shadi Yaghi, MD\textsuperscript{c}; Philip
Haines, MD\textsuperscript{a}

\textbf{Affiliations:}

\textsuperscript{a}Department of Cardiology, Alpert Medical School of
Brown University, Providence, RI, USA

\textsuperscript{b}Department of Ultrasound, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China

\textsuperscript{c}Department of Neurology, Alpert Medical School of
Brown University, Providence, RI, USA

\textsuperscript{d}Lifespan Biostatistics, Epidemiology and Research
Design, Rhode Island Hospital, Providence, RI, USA

\textsuperscript{e}Stanford Cardiovascular Institute, Stanford
University, Palo Alto, California

\textsuperscript{f}Division of Cardiovascular Medicine, Department of
Medicine, University of Massachusetts Medical School, Worcestor, MA, USA

\textsuperscript{g}Department of Pulmonary, Critical Care, and Sleep
Medicine, Alpert Medical School of Brown University, Providence, RI, US

\textbf{Total word count:} 3,595 words; \textbf{Abstract word count:}263
words; \textbf{Tables:} 5; \textbf{Figures:} 3

\textbf{Address for Correspondence:}

Philip Haines, MD

Lifespan Cardiovascular Institute

593-Eddy Street, Providence, Rhode Island, 02903

Email: philip\_haines@brown.edu

Phone:+1-267-226-2342

Tweet: Reduced Left Atrial Strain is associated with ESUS and AF
detection on cardiac monitoring. \#Left Atrial Strain, \#ESUS, \#Atrial
Fibrillation

Data sharing: It is available on reasonable request to the corresponding
author

Funding: There are no funding sources to be disclosed.

Disclosure: Dr. Yaghi reports unpaid research collaboration with
Medtronic

Ethics approval statement: The study was approved by the Lifespan
Institutional Review Board

Patient consent: It was waived due to retrospective nature of this study

\textbf{Abstract}

\textbf{Background:} Atrial cardiopathy is a proposed mechanism of
embolic stroke of undetermined source (ESUS). Left atrial (LA) strain
may identify early atrial cardiopathy prior to structural changes. We
aim to study the associations between LA strain, ESUS, and atrial
fibrillation (AF) detection in ESUS.

\textbf{Methods:} The study population included patients with ESUS and
non-cardioembolic (NCE) stroke presenting to statewide stroke center
between January 2016 and June 2017 who underwent transthoracic
echocardiography. Speckle tracking echocardiography (STE) was used to
measure the 3 phases of LA strain (reservoir, conduit, and contractile).
Binary logistic regression analysis was performed to determine the
associations between LA strain and stroke subtype (ESUS vs. NCE) as well
as follow-up detection of AF in ESUS patients.

\textbf{Results:} We identified 656 patients, 307 with ESUS and 349 with
NCE. In binary logistic regression, the lowest tertiles of LA reservoir
(adjusted OR 1.944, 95\% CI 1.266-2.986, p = 0.002), contractile (aOR
1.568, 95\% CI 1.035-2.374, p = 0.034), and conduit strain (aOR 2.288,
95\% CI 1.448-3.613, p = 0.001) were more likely to be significantly
associated with ESUS compared to NCE stroke. Among all ESUS patients,
the lowest tertiles of LA reservoir strain (OR 2.534, 95\% CI
1.029-6.236, p = 0.043), contractile strain (OR 2.828, 95\% CI
1.158-6.903, p = 0.022), and conduit strain (OR 2.614, 95\% CI
1.003-6.815, p = 0.049) were significantly associated with subsequent
detection of AF.

\textbf{Conclusion:} Reduced LA strain is associated with ESUS
occurrence and AF detection in ESUS patients. Therefore, quantification
of LA strain in ESUS patients may improve risk stratification and guide
secondary prevention strategies.

\textbf{Key words:} Left Atrial Strain; Atrial Cardiopathy; ESUS; Atrial
Fibrillation;



\textbf{Clinical Perspectives:}

What is known:

Speckle tracking echocardiography is a sensitive and reproducible
technique that identifies subtle changes in the atrial biomechanics
prior to any significant volumetric changes.

LA dysfunction is associated with ESUS stroke subtype

What this study adds:

This study adds to the growing body of evidence suggesting early
recognition of atrial cardiopathy in ESUS stroke subtype using speckle
tracking echocardiography.

It also provides evidence that routine quantification of LA strain in
ESUS patients may identify a subset of ESUS patients that may benefit
from intensive cardiac arrhythmia surveillance and potential
anticoagulation therapy.



\emph{Introduction:}

Ischemic stroke accounts for 87\% of all strokes\textsuperscript{1}, and
cryptogenic stroke constitutes approximately 30-40\% of all ischemic
strokes\textsuperscript{2, 3}\{Perera, 2022 \#584\}. Embolic Stroke of
Undetermined Source (ESUS) is a subtype of cryptogenic stroke in which
there is embolic-appearing infarction on CT and/or MRI without an
identifiable etiology despite standard diagnostic
evaluation\textsuperscript{4}. It is associated with a high
recurrence\textsuperscript{5, 6}; thus, in addition to risk factor
modification, identifying and targeting the primary causal mechanisms
may improve secondary prevention strategies\textsuperscript{7}. Better
characterization of left atrial (LA) structure and function may
elucidate a mechanistic pathway in the development of cryptogenic
stroke. Previous studies have shown an association of left atrial
enlargement (LAE)\textsuperscript{8, 9} and left atrial volume index
(LAVI)\textsuperscript{10} with ESUS stroke subtype as compared to
non-cardioembolic (NCE) stroke subtype. However, LA chamber remodeling
and biomechanical dysfunction precede volumetric changes in LA
chamber\textsuperscript{11}. Speckle tracking echocardiography (STE) and
strain analysis have been shown to detect these early signals prior to
structural changes found on traditional imaging
methods\textsuperscript{12-14}. Atrial cardiopathy has been
characterized as a time-dependent adaptive structural remodeling with
electrical and mechanical dysfunction causing stasis of blood. It may
provide a potential substrate for the development of thrombus even in
the absence of atrial enlargement or fibrillation\textsuperscript{13,
15}. Atrial fibrosis, an early sign of atrial remodeling, correlates
inversely with LA strain\textsuperscript{16, 17} and is reported more
frequently in ESUS compared NCE subtype\textsuperscript{18}. A recent
single-center study showed the association of LA strain and stroke
subtypes including cryptogenic stroke\textsuperscript{19}.

The goal of our study is to investigate the relationship between LA
strain and stroke, specifically ESUS and NCE stroke subtypes, in a
geographically distinct population using a comprehensive stroke
database. Additionally, we aim to examine the relationship between LA
strain and future atrial fibrillation (AF) events in ESUS patients.

\emph{Methods:}

This study was approved by Lifespan Institutional Review Board. Informed
consent was waived as this is a retrospective study.

The study population included all patients presenting to a comprehensive
regional stroke center with a primary diagnosis of ischemic stroke
between January 2016 and June 2017. All patients enrolled in the stroke
database underwent standard ischemic stroke evaluation including
laboratory testing, neuroimaging, 12-lead EKG, transthoracic
echocardiography (TTE), and cardiac telemetry monitoring for at least 24
hours. The stroke subtype was assigned by a vascular neurologist, who
was following the patients over the course of index hospitalization,
based on the TOAST criteria\textsuperscript{20} and ESUS subtype was
defined based on the ESUS consensus criteria\textsuperscript{21}. This
data was extracted by chart review. Stroke subtype was divided into two
categories: ESUS and NCE. Demographic variables, vascular risk factors,
and laboratory covariates (age, sex, history of hypertension, diabetes
mellitus, hyperlipidemia, coronary artery disease, congestive heart
failure, renal disease, systolic blood pressure, smoking status,
National Institutes of Health Stroke Scale (NIHSS) score) were also
extracted and collected on the Research Electronic Data Capture database
(REDCap; Vanderbilt University, Nashville, TN). All ESUS patients were
given a prescription of cardiac event monitor (CEM) as per guidelines
regardless of symptoms. Those with negative CEM results were given
implantable loop recorders (ILR). The presence of AF was defined as
identification of AF for more than 30 seconds on monitoring.

Patients with a history of atrial fibrillation or any of the following
conditions were excluded: moderate to severe valve disease (as
determined by clinical echocardiography reports), a left ventricular
ejection fraction (LVEF) of less than 40\%, pericardial effusion causing
tamponade, any type of congenital heart disease, a prosthetic heart
valve, left ventricular assist device, or poor image quality (LA chamber
foreshortening, or unclear atrial walls etc.) to perform STE analysis
(Figure 1).

\textbf{Echocardiographic Parameters}

2D TTE was performed either during the index hospitalization or within
three months of the indexed ischemic stroke. Studies were performed
according to the guidelines from the American Society of
Echocardiography (ASE)\textsuperscript{22}, and reports were generated
by cardiologists board-certified in echocardiography. Phasic LA function
was quantified off-line using TOMTEC (Chicago,
IL)\textsuperscript{23}according to guidelines from the European
Association of Cardiovascular Imaging (EACVI)/ASE Task
Force\textsuperscript{24}. The procedure entailed a careful selection of
TTE images capturing optimal views of the left atrium (LA).
Specifically, the LA-focused apical 4-chamber (A4-C) and 2-chamber
(A2-C) views providing the clearest visualization were obtained. In
cases where the A4-C view did not provide sufficient clarity, the A2-C
view was used independently. After thorough assessment of multiple
cardiac cycles, a single cardiac cycle presenting the best image quality
was chosen. The LA endocardial border was manually traced from mitral
annulus at one side, extrapolating across the pulmonary veins and atrial
appendage orifices to the opposite side in the end-diastolic and
end-systolic phases of a cardiac cycle (Figure 2). This generated
average atrial strain curve with two peaks. LA reservoir strain was
calculated by measuring the peak atrial longitudinal strain (PALS) at
the end of ventricular systole, corresponding with the first peak. LA
contractile strain was calculated by measuring the peak atrial
contraction strain (PACS) at the onset of atrial contraction,
corresponding with the second peak. Conduit (passive emptying) strain
was calculated by the difference between the PALS and
PACS\textsuperscript{12, 24} (Figure 2). The quality of wall tracking
was recorded according to the number of walls appropriately tracked.
Echocardiography analysis was blinded to stroke subtype and outcomes.

\textbf{Statistical Analysis}

We compared demographic, clinical, and laboratory data between the two
groups using t-tests for continuous variables and Fisher's exact tests
for categorical variables. LA strain was divided into three
components---LA reservoir, conduit, and contractile---to determine the
association of each phase of atrial function with stroke subtypes.
Multivariable logistic regression analysis adjusting for covariates was
performed. The first model was adjusted for age and sex. The second
model was adjusted for covariates in model 1 plus systolic blood
pressure, history of congestive heart failure defined as heart failure
with mid-range and preserved ejection fraction according to the
guidelines from the Heart Failure Society of
America\textsuperscript{25}, and NIHSS. LA strain components (reservoir,
conduit, and contractile) were assessed both as linear and tertile
categorical variables to simplify the analysis for easier interpretation
and to study the trend within the LA strain dataset. All ESUS patients
were give a prescription of cardiac event monitor (CEM). Those with
negative CEM were given implantable loop recorders (ILR). The presence
of AF was defined as identification of AF for more than 30 seconds on
monitoring.

We compared three phases of LA strain between all ESUS patients with and
without AF detection using t-tests. The association between LA strain
and detection of AF was assessed using logistic regression analysis.
Sensitivity analyses were performed adjusting for age, focusing only on
ESUS patients who received cardiac monitoring, and focusing only on ESUS
patients found to have AF on cardiac monitoring to compare differences
in LA strain between those with an AF burden of less than 24 hours
versus greater than or equal to 24 hours. Analysis was performed using
STATA SE v17 with a p-value \textless{} 0.05 as statistically
significant.

\emph{Results:}

Baseline Characteristics

In total, 1313 eligible patients were screened for inclusion based on
the criteria mentioned above. Among the excluded subjects, those with
uninterpretable echocardiograms stood out as the most notable group. Due
to the inherent limitations of clinical research and the challenges
associated with speckled tracking strain analysis on clinical
echocardiograms, meticulous care was taken to ensure accurate tracking
of the LA chamber walls. Consequently, approximately 22\% of the
echocardiograms were deemed uninterpretable and subsequently excluded
from the final cohort of the analytic sample (Figure 1). The criteria
for defining echocardiograms as uninterpretable included foreshortening
of the LA chamber view, inadequate visibility of one or more walls of
the LA chamber for endocardial tracing, and echocardiograms with a wall
tracking score of 1 where more than one endocardial wall did not show
appropriate tracking despite its adequate gross visibility.

Among the 656 total stroke patients utilized in the study sample, 349
patients were classified as NCE and 307 as ESUS. Among the NCE patients,
208 had large artery atherosclerosis, 87 had small vessel disease, and
54 had other determined or undetermined etiology. The clinical
characteristics of the NCE cohort and ESUS cohort were largely similar,
except for a few notable differences. The NCE cohort had a higher
percentage of males (61.3\% vs. 48.5\%, p = 0.001) and a higher mean
systolic blood pressure in mm Hg (152.2 + 29.5 vs. 144.6 + 26.5, p =
0.001). Conversely, the NCE cohort had a lower percentage of individuals
with a history of congestive heart failure (0.6\% vs. 4.2\%, p = 0.003)
and a lower median NIHSS (National Institutes of Health Stroke Scale)
score (7 vs. 10, p \textless{} 0.001) compared to the ESUS cohort (Table
1).

On echocardiography analysis, compared to NCE, patients with ESUS had a
significantly lower LA reservoir strain (32.0 \selectlanguage{ngerman}± 16.1 vs. 36.7 ± 17.9, p
\textless{} 0.001), LA contractile strain (15.5 ± 9.6 vs. 17.4 ± 10.7, p
= 0.018), and LA conduit strain (16.5 ± 10.7 vs. 19.3 ± 11.5, p = 0.001)
(Table 1).

Multivariable Analysis of Associations between LA Reservoir,
Contractile, and Conduit Strain and ESUS

On binary logistic regression analysis utilizing LA strain as tertiles,
the lowest tertiles (Tertile 1) of LA reservoir (OR 1.860, 95\% CI
1.272-2.721, p = 0.001), contractile (OR 1.845, 95\% CI 1.261-2.699, p =
0.002), and conduit (OR 1.930, 95\% CI 1.319-2.825, p = 0.001) strain
were associated with ESUS compared to NCE (Table 2). After adjustment,
low LA reservoir (OR 1.944, 95\% CI 1.266-2.986, p = 0.002), contractile
(OR 1.568, 95\% CI 1.035-2.374, p = 0.034), and conduit (OR 2.288, 95\%
CI 1.448-3.613, p = 0.001) strain continued to be significantly
associated with ESUS compared to NCE.

On binary logistic regression analyses utilizing LA strain as continuous
variables, there was an inverse relationship of higher LA reservoir (OR
0.983, 95\% CI 0.974-0.993, p = 0.001) and conduit (OR 0.977, 95\% CI
0.962-0.991, p = 0.001) strain and ESUS compared to NCE in the
unadjusted model, and these findings persisted after adjustment
(reservoir strain OR 0.985, 95\% CI 0.974-0.995, p = 0.005; conduit
strain OR 0.971, 95\% CI 0.955-0.988, p = 0.001) (Table 2). There was
also an inverse association of higher LA contractile strain and ESUS
compared to NCE in the unadjusted model (OR 0.982, 95\% CI 0.966-0.997,
p = 0.019); though the effect size remained the same, the association
was no longer significant after adjustment for confounding variables (OR
0.990, 95\% CI 0.973-1.007, p = 0.239).

Atrial Fibrillation Detection in ESUS patients

All 307 patients with ESUS were given a prescription for CEM. Out of the
307 patients, 155 completed the monitoring process successfully. The
rest either declined or were unable to complete the process. Of the 155
patients who completed monitoring, 88 only had a 30-day CEM and 67 also
had successful ILR in addition to the CEM, while the rest either
declined or were lost to follow-up. Among all 307 ESUS patients, AF was
detected in 32 patients who received scheduled cardiac monitoring.
Additionally, 7 patients who did not receive scheduled cardiac
monitoring were incidentally found to have AF in subsequent outpatient
or hospital visits. Patients with AF detected had significantly
decreased mean LA reservoir strain (25.15±13.57 vs. 32.95±16.20, p =
0.005), LA contractile strain (12.24±10.00 vs. 15.95±9.41, p = 0.023),
and LA conduit strain (12.91±6.45 vs. 17.00±11.09, p = 0.025) compared
to patients without AF detected (Table 3). In the sensitivity analysis
using the 32 ESUS patients found to have AF on cardiac monitoring, there
was no significant difference in LA reservoir strain (26.15\emph{+}
15.25 vs. 26.50\emph{+} 12.17, p = 0.953), LA contractile strain
(12.79\emph{+} 11.90 vs. 11.56\emph{+} 6.74, p = 0.785), and LA conduit
strain (13.36 \emph{+} 6.31 vs. 14.94\emph{+} 7.12, p = 0.557) between
those with an AF burden of less than 24 hours compared to those with an
AF burden of greater than or equal to 24 hours likely due to small
sample size (Table 4). In the sensitivity analysis using only the 155
ESUS patients who received cardiac monitoring, the effect size of LA
strain remained stable, but significance was also lost likely due to
small sample size (Supplementary Table 1).

Multivariable Analysis of Associations between LA strain and Atrial
Fibrillation Detection in ESUS patients

Among all ESUS patients, in binary logistic analysis using LA strain as
tertiles, the lowest tertile of strain values (Tertile 1) showed
significant association of LA reservoir strain (unadjusted OR 2.534,
95\% CI 1.029-6.236, p = 0.043), LA contractile strain (unadjusted OR
2.828, 95\% CI 1.158-6.903, p = 0.022) and LA conduit strain (unadjusted
OR 2.614, 95\% CI 1.003-6.815, p = 0.049) with AF detection (Table 5).
When utilizing LA strain as a continuous variable, decreased LA
reservoir strain (unadjusted OR 0.957, 95\% CI 0.929-0.987, p = 0.005),
LA contractile strain (unadjusted OR 0.949, 95\% CI 0.907-0.993, p =
0.025), and LA conduit strain (unadjusted OR 0.952, 95\% CI 0.912-0.994,
p = 0.025) were significantly associated with detection of AF (Table 5).
Findings remain unchanged in the sensitivity analyses adjusting for age.
In the sensitivity analysis using only the 155 ESUS patients who
received cardiac monitoring, the effect size of LA strain remained
stable but significance was lost likely due to small sample size
(Supplementary Table 2).

\emph{Discussion:}

In this large single-center retrospective observational study of atrial
cardiopathy and stroke, we found that atrial dysfunction as evidenced by
reduced left atrial strain was associated with ESUS stroke when compared
to NCE strokes. In addition, reduced LA strain was predictive of future
detection of AF in these ESUS patients.

\textbf{Clinical Implications}

LA remodeling is a time-dependent adaptive change in the atrial
cardiomyocyte that is followed by biomechanical
changes\textsuperscript{17} affecting all the three phases of LA
function \textsuperscript{26}. Thus, LA strain is a surrogate of atrial
fibrosis and remodeling\textsuperscript{16}. Previous studies have shown
a correlation between enlarged LA chamber size with adverse
cardiovascular outcomes including the risk of strokes and
arrhythmias\textsuperscript{27, 28}. Our study shows the association of
reduced LA strain with ESUS compared to NCE, further potentiating
previously reported LA strain's association with cryptogenic
stroke\textsuperscript{13, 19}. In addition, it also demonstrates that
reduced LA conduit and contractile strains are more commonly associated
with ESUS compared to NCE stroke. This may be explained by underlying
atrial fibrosis, remodeling, and biomechanical dysfunction causing
stiffening of the atrial chamber, which impairs the compliance and
booster-pump function of the atrium leading to atrial reservoir and
contractile dysfunction. LA reservoir strain has been shown to be a
predictor of thrombus formation in LA appendage in patients with sinus
rhythm\textsuperscript{29}. Our study adds to the existing literature
showing significant association of all phases of reduced LA strain with
ESUS subtype in patients in sinus rhythm with midrange and normal LVEF
and in the absence of acute heart failure\textsuperscript{30}.

Furthermore, the extent of atrial fibrosis inversely correlates with LA
reservoir strain in AF irrespective of chamber
size\textsuperscript{31}and independently predicts progression from
paroxysmal AF to persistent AF\textsuperscript{32}. Our study
demonstrates the association of all phases of reduced LA strain with AF
in ESUS patients. This adds to the previously reported association of AF
with reduced LA strain in cryptogenic stroke
patients\textsuperscript{33} . However, our study demonstrates the
association of AF with ESUS subtype, which is a more enriched population
with a high recurrence rate of stroke within the spectrum of cryptogenic
stroke subtype. Our findings also confirm recently published studies
showing contractile strain as an emerging echocardiographic parameter
for predicting AF in cryptogenic stroke patients\textsuperscript{34,
35}. This provides a mechanistic pathway for the occurrence of ESUS,
where atrial cardiomyopathy and biomechanical dysfunction provide a
potential substrate for embolic source and also increases the likelihood
of AF detection.

Recent trials, NAVIGATE ESUS\textsuperscript{5} and RE-SPECT
ESUS\textsuperscript{6}, did not show any benefit of oral anticoagulants
over antiplatelet therapy for secondary prevention in ESUS patients
overall. This is likely explained by significant heterogeneity in the
underlying mechanisms of the ESUS subtype. However, anticoagulation may
not work for all ESUS patients but may benefit those with atrial
cardiopathy\textsuperscript{36} and those with ESUS and moderate to
severe LV dysfunction\textsuperscript{37}.

Our study demonstrates the utility of LA strain as a measure of early
atrial cardiopathy in identifying the subset of ESUS patients that can
benefit from a more rigorous cardiovascular risk factor modification,
intensive cardiac arrhythmia surveillance with prolong atrial
fibrillation monitoring, and potentially anticoagulation therapy.

Mechanism of Association

A number of potential mechanisms for ESUS have been identified which
include substenotic or aortic arch atherosclerosis, patent foramen
ovale, occult paroxysmal AF, LA cardiopathy and LV
dysfunction\textsuperscript{7, 38}.

Notably, atrial cardiopathy involves a complex interplay of electrical
and biomechanical changes at cellular and molecular levels causing
atrial remodeling and electro-mechanical
dysfunction\textsuperscript{39-41}. These changes lead to stasis of
blood promoting thrombus formation in the LA chamber and at sites of
adversely remodeled endocardial borders, thereby predisposing to
thrombo-embolic events. To assess atrial dysfunction, different
techniques have been utilized, including echocardiography,
electrocardiography (EKG), and biomarker analysis. Enlarged left atrial
chamber, prolongation of the peak P wave terminal force and PR interval
on EKG\textsuperscript{42, 43}, and elevated biomarkers like cardiac
troponin and N-Terminal pro-Brain Natriuretic Peptide have been
associated with myocardial injury, atrial remodeling, fibrosis, and
dysfunction\textsuperscript{44}. These factors have been identified as
potential risk factors for thrombus formation and can independently
predict future embolic events in patients with non-valvular atrial
fibrillation\textsuperscript{44, 45}. However, STE can detect atrial
dysfunction at an earlier stage, even before the changes identified by
these other techniques become apparent. In addition, cardiac magnetic
resonance (CMR) imaging has shown comparable amounts of fibrosis in
patients with ESUS and those with AF, regardless of prior stroke history
in AF group. Interestingly, both these groups were also found to have
higher LA fibrosis than those with lacunar strokes \textsuperscript{46}.
Therefore, LA strain analysis using STE may be a useful tool to further
risk stratify ESUS patients for recurrence and future AF detection.

\textbf{Limitations:}

Our study sample was extracted from a single medical center, which may
limit the generalizability of our results. Out of 307 ESUS patients,
only 155 patients completed cardiac monitoring, and AF was detected in
32 of these patients. This small sample size may limit the significance
of our associations. For strain analysis, approximately 22\% of the
total eligible patients had suboptimal images, which may lead to
potential bias in our results. This is due to the nature of our
clinical-based research, which utilized clinical echocardiographic
images instead of dedicated research echocardiograms. In addition,
several different software options are available for STE including
TomTec, which may contribute to potential variability in
echocardiographic measurements. However, our study reported comparative
measurements instead of absolute values, thus attenuating possible
variability. Finally, we did not use absolute values for abnormal LA
strain because these do not currently exist for the stroke population to
predict neurovascular clinical outcomes and is an ongoing area of
research.

\textbf{Conclusion:}

In conclusion, our study adds to the existing body of evidence by
reaffirming the established associations between atrial cardiopathy,
stroke subtypes, and atrial fibrillation (AF) in a geographically
distinct population. Our findings highlight the association between
lower LA strain and ESUS stroke subtype, as well as the higher
prevalence of AF in ESUS patients, which supports the hypothesis that
atrial cardiopathy plays an important role in the mechanistic pathway of
ESUS. Consequently, we propose that incorporating routine quantification
of LA strain may be a valuable tool for clinicians in risk
stratification and selecting appropriate secondary prevention strategies
for ESUS patients identified at high risk of recurrence.

\textbf{References}

1. Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS,
et al. Heart disease and stroke statistics-2022 update: A report from
the american heart association. \emph{Circulation} . 2022;145:e153-e639

2. Perera KS, de Sa Boasquevisque D, Rao-Melacini P, Taylor A, Cheng A,
Hankey GJ, et al. Evaluating rates of recurrent ischemic stroke among
young adults with embolic stroke of undetermined source: The young esus
longitudinal cohort study. \emph{JAMA Neurol} . 2022;79:450-458

3. Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic stroke
of undetermined source: A systematic review and clinical
update.\emph{Stroke} . 2017;48:867-872

4. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O'Donnell MJ,
et al. Embolic strokes of undetermined source: The case for a new
clinical construct. \emph{Lancet Neurol} . 2014;13:429-438

5. Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD,
et al. Rivaroxaban for stroke prevention after embolic stroke of
undetermined source. \emph{N Engl J Med} . 2018;378:2191-2201

6. Diener HC, Sacco RL, Easton JD, Granger CB, Bernstein RA, Uchiyama S,
et al. Dabigatran for prevention of stroke after embolic stroke of
undetermined source. \emph{N Engl J Med} . 2019;380:1906-1917

7. Yaghi S, Bernstein RA, Passman R, Okin PM, Furie KL. Cryptogenic
stroke: Research and practice. \emph{Circ Res} . 2017;120:527-540

8. Yaghi S, Bartz TM, Kronmal R, Kamel H, Gottdiener J, Longstreth WT,
Jr., et al. Left atrial diameter and vascular brain injury on mri: The
cardiovascular health study. \emph{Neurology} . 2018;91:e1237-e1244

9. Yaghi S, Moon YP, Mora-McLaughlin C, Willey JZ, Cheung K, Di Tullio
MR, et al. Left atrial enlargement and stroke recurrence: The northern
manhattan stroke study. \emph{Stroke} . 2015;46:1488-1493

10. Jordan K, Yaghi S, Poppas A, Chang AD, Mac Grory B, Cutting S, et
al. Left atrial volume index is associated with cardioembolic stroke and
atrial fibrillation detection after embolic stroke of undetermined
source. \emph{Stroke} . 2019;50:1997-2001

11. Mondillo S, Cameli M, Caputo ML, Lisi M, Palmerini E, Padeletti M,
et al. Early detection of left atrial strain abnormalities by
speckle-tracking in hypertensive and diabetic patients with normal left
atrial size. \emph{J Am Soc Echocardiogr} . 2011;24:898-908

12. Hoit BD. Left atrial size and function: Role in prognosis. \emph{J
Am Coll Cardiol} . 2014;63:493-505

13. Leong DP, Joyce E, Debonnaire P, Katsanos S, Holman ER, Schalij MJ,
et al. Left atrial dysfunction in the pathogenesis of cryptogenic
stroke: Novel insights from speckle-tracking echocardiography. \emph{J
Am Soc Echocardiogr} . 2017;30:71-79 e71

14. Leong DP, Penhall A, Perry R, Shirazi M, Altman M, Chong D, et al.
Speckle-tracking strain of the left atrium: A transoesophageal
echocardiographic validation study. \emph{Eur Heart J Cardiovasc
Imaging} . 2013;14:898-905

15. Ning Y, Tse G, Luo G, Li G. Atrial cardiomyopathy: An emerging cause
of the embolic stroke of undetermined source. \emph{Front Cardiovasc
Med} . 2021;8:674612

16. Kuppahally SS, Akoum N, Burgon NS, Badger TJ, Kholmovski EG,
Vijayakumar S, et al. Left atrial strain and strain rate in patients
with paroxysmal and persistent atrial fibrillation: Relationship to left
atrial structural remodeling detected by delayed-enhancement
mri.\emph{Circ Cardiovasc Imaging} . 2010;3:231-239

17. Her AY, Choi EY, Shim CY, Song BW, Lee S, Ha JW, et al. Prediction
of left atrial fibrosis with speckle tracking echocardiography in mitral
valve disease: A comparative study with histopathology. \emph{Korean
Circ J} . 2012;42:311-318

18. Fonseca AC, Alves P, Inacio N, Marto JP, Viana-Baptista M, Pinho
EMT, et al. Patients with undetermined stroke have increased atrial
fibrosis: A cardiac magnetic resonance imaging study. \emph{Stroke} .
2018;49:734-737

19. Bhat A, Chen HHL, Khanna S, Mahajan V, Gupta A, Burdusel C, et al.
Diagnostic and prognostic value of left atrial function in
identification of cardioembolism and prediction of outcomes in patients
with cryptogenic stroke. \emph{J Am Soc Echocardiogr} .
2022;35:1064-1076

20. Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon
DL, et al. Classification of subtype of acute ischemic stroke.
Definitions for use in a multicenter clinical trial. Toast. Trial of org
10172 in acute stroke treatment. \emph{Stroke} . 1993;24:35-41

21. Perera KS, Vanassche T, Bosch J, Giruparajah M, Swaminathan B,
Mattina KR, et al. Embolic strokes of undetermined source: Prevalence
and patient features in the esus global registry. \emph{Int J Stroke} .
2016;11:526-533

22. Mitchell C, Rahko PS, Blauwet LA, Canaday B, Finstuen JA, Foster MC,
et al. Guidelines for performing a comprehensive transthoracic
echocardiographic examination in adults: Recommendations from the
american society of echocardiography. \emph{J Am Soc Echocardiogr} .
2019;32:1-64

23. Wang Y, Li Z, Fei H, Yu Y, Ren S, Lin Q, et al. Left atrial strain
reproducibility using vendor-dependent and vendor-independent
software.\emph{Cardiovasc Ultrasound} . 2019;17:9

24. Badano LP, Kolias TJ, Muraru D, Abraham TP, Aurigemma G, Edvardsen
T, et al. Standardization of left atrial, right ventricular, and right
atrial deformation imaging using two-dimensional speckle tracking
echocardiography: A consensus document of the eacvi/ase/industry task
force to standardize deformation imaging. \emph{Eur Heart J Cardiovasc
Imaging} . 2018;19:591-600

25. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM,
et al. 2022 aha/acc/hfsa guideline for the management of heart failure:
A report of the american college of cardiology/american heart
association joint committee on clinical practice
guidelines.\emph{Circulation} . 2022;145:e895-e1032

26. Barbier P, Solomon SB, Schiller NB, Glantz SA. Left atrial
relaxation and left ventricular systolic function determine left atrial
reservoir function. \emph{Circulation} . 1999;100:427-436

27. Barnes ME, Miyasaka Y, Seward JB, Gersh BJ, Rosales AG, Bailey KR,
et al. Left atrial volume in the prediction of first ischemic stroke in
an elderly cohort without atrial fibrillation. \emph{Mayo Clin Proc} .
2004;79:1008-1014

28. Bouzas-Mosquera A, Broullon FJ, Alvarez-Garcia N, Mendez E, Peteiro
J, Gandara-Sambade T, et al. Left atrial size and risk for all-cause
mortality and ischemic stroke. \emph{CMAJ} . 2011;183:E657-664

29. Kurzawski J, Janion-Sadowska A, Zandecki L, Piatek L, Koziel D,
Sadowski M. Global peak left atrial longitudinal strain assessed by
transthoracic echocardiography is a good predictor of left atrial
appendage thrombus in patients in sinus rhythm with heart failure and
very low ejection fraction - an observational study. \emph{Cardiovasc
Ultrasound} . 2020;18:7

30. Park JH, Hwang IC, Park JJ, Park JB, Cho GY. Left atrial strain to
predict stroke in patients with acute heart failure and sinus
rhythm.\emph{J Am Heart Assoc} . 2021;10:e020414

31. Kojima T, Kawasaki M, Tanaka R, Ono K, Hirose T, Iwama M, et al.
Left atrial global and regional function in patients with paroxysmal
atrial fibrillation has already been impaired before enlargement of left
atrium: Velocity vector imaging echocardiography study. \emph{Eur Heart
J Cardiovasc Imaging} . 2012;13:227-234

32. Yoon YE, Oh IY, Kim SA, Park KH, Kim SH, Park JH, et al.
Echocardiographic predictors of progression to persistent or permanent
atrial fibrillation in patients with paroxysmal atrial fibrillation (e6p
study). \emph{J Am Soc Echocardiogr} . 2015;28:709-717

33. Pathan F, Sivaraj E, Negishi K, Rafiudeen R, Pathan S, D'Elia N, et
al. Use of atrial strain to predict atrial fibrillation after cerebral
ischemia. \emph{JACC Cardiovasc Imaging} . 2018;11:1557-1565

34. Kawakami H, Ramkumar S, Pathan F, Wright L, Marwick TH. Use of
echocardiography to stratify the risk of atrial fibrillation: Comparison
of left atrial and ventricular strain. \emph{Eur Heart J Cardiovasc
Imaging} . 2020;21:399-407

35. Bertelsen L, Diederichsen SZ, Haugan KJ, Brandes A, Graff C, Krieger
D, et al. Left atrial volume and function assessed by cardiac magnetic
resonance imaging are markers of subclinical atrial fibrillation as
detected by continuous monitoring. \emph{Europace} . 2020;22:724-731

36. Longstreth WT, Jr., Kronmal RA, Thompson JL, Christenson RH, Levine
SR, Gross R, et al. Amino terminal pro-b-type natriuretic peptide,
secondary stroke prevention, and choice of antithrombotic
therapy.\emph{Stroke} . 2013;44:714-719

37. Merkler AE, Pearce LA, Kasner SE, Shoamanesh A, Birnbaum LA, Kamel
H, et al. Left ventricular dysfunction among patients with embolic
stroke of undetermined source and the effect of rivaroxaban vs aspirin:
A subgroup analysis of the navigate esus randomized clinical
trial.\emph{JAMA Neurol} . 2021;78:1454-1460

38. Ntaios G. Embolic stroke of undetermined source: Jacc review topic
of the week. \emph{J Am Coll Cardiol} . 2020;75:333-340

39. Goette A, Kalman JM, Aguinaga L, Akar J, Cabrera JA, Chen SA, et al.
Ehra/hrs/aphrs/solaece expert consensus on atrial cardiomyopathies:
Definition, characterization, and clinical implication. \emph{Europace}
. 2016;18:1455-1490

40. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological
mechanisms of atrial fibrillation: A translational
appraisal.\emph{Physiol Rev} . 2011;91:265-325

41. Dimitri H, Ng M, Brooks AG, Kuklik P, Stiles MK, Lau DH, et al.
Atrial remodeling in obstructive sleep apnea: Implications for atrial
fibrillation. \emph{Heart Rhythm} . 2012;9:321-327

42. Tiffany Win T, Ambale Venkatesh B, Volpe GJ, Mewton N, Rizzi P,
Sharma RK, et al. Associations of electrocardiographic p-wave
characteristics with left atrial function, and diffuse left ventricular
fibrosis defined by cardiac magnetic resonance: The primeri
study.\emph{Heart Rhythm} . 2015;12:155-162

43. Montalvo M, Tadi P, Merkler A, Gialdini G, Martin-Schild S,
Navalkele D, et al. Pr interval prolongation and cryptogenic stroke: A
multicenter retrospective study. \emph{J Stroke Cerebrovasc Dis} .
2017;26:2416-2420

44. Yaghi S, Kamel H, Elkind MSV. Atrial cardiopathy: A mechanism of
cryptogenic stroke. \emph{Expert Rev Cardiovasc Ther} . 2017;15:591-599

45. Leung DY, Black IW, Cranney GB, Hopkins AP, Walsh WF. Prognostic
implications of left atrial spontaneous echo contrast in nonvalvular
atrial fibrillation. \emph{J Am Coll Cardiol} . 1994;24:755-762

46. Kuhnlein P, Mahnkopf C, Majersik JJ, Wilson BD, Mitlacher M,
Tirschwell D, et al. Atrial fibrosis in embolic stroke of undetermined
source: A multicenter study. \emph{Eur J Neurol} . 2021;28:3634-3639



\textbf{Table 1. Baseline Characteristics based on Stroke Subtype}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Variable}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{NCE} \textbf{(n = 349)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{ESUS} \textbf{(n = 307)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{p-value}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age (mean \emph{+} SD)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
64.6 \selectlanguage{ngerman}± 13.9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
65.8 \selectlanguage{ngerman}± 14.8\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.298\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sex (\% men)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
214 (61.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
149 (48.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hypertension (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
234 (67.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
211 (68.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.723\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Diabetes (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
85 (24.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
85 (27.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.376\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hyperlipidemia (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
152 (43.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
146 (47.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.371\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Coronary Artery Disease (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
52 (14.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
43 (14.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.723\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Congestive Heart Failure (\%)*\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (0.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
13 (4.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.003\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Renal Disease (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
18 (5.16\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
21 (6.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.383\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Current Smoker (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
94 (26.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
69 (22.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.158\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Systolic blood pressure\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
152.2 \selectlanguage{ngerman}± 29.5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
144.6 \selectlanguage{ngerman}± 26.5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NIHSS (median, IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (3-15)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10 (4-19)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Left Atrial Reservoir Strain (mean \emph{+} SD)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
36.7 \selectlanguage{ngerman}± 17.9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
32.0 \selectlanguage{ngerman}± 16.1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Left Atrial Contractile Strain (mean \emph{+} SD)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
17.4 \selectlanguage{ngerman}± 10.7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15.5 \selectlanguage{ngerman}± 9.6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.018\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Left Atrial Conduit Strain (mean \emph{+} SD)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19.3 \selectlanguage{ngerman}± 11.5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16.5 \selectlanguage{ngerman}± 10.7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.001\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

NCE: Non Cardioembolic. ESUS: Embolic Stroke of Undetermined Source.
NIHSS: National Institute of Health Stroke Scale.

*Fisher's exact test used

\textbf{Table 2. Multivariate Model Showing Associations between LA
Reservoir, Contractile, and Conduit Strain in ESUS compared to NCE}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Overall}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Tertile 1}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Tertile 2}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Tertile 3}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Reservoir Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Reservoir Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Reservoir Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Reservoir Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Reservoir Strain}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Range}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7.20 -- 105.23\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7.20 -- 25.48\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
25.55 -- 36.64\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
36.66 -- 105.23\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Unadjusted \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.983 (0.974-0.993) p = 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.860 (1.272-2.721) p = 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.314 (0.898-1.921) p = 0.159\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Model 1 \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.986 (0.976-0.996) p = 0.004\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.741 (1.178-2.572) p = 0.005\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.273 (0.868-1.867) p = 0.216\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Model 2 \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.985 (0.974-0.995) p = 0.005\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.944 (1.266-2.986) p = 0.002\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.240 (0.818-1.881) p = 0.311\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Contractile Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Contractile Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Contractile Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Contractile Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Contractile Strain}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Range}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.58 -- 68.90\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.58 -- 11.18\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11.23 -- 18.16\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
18.18 -- 68.90\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Unadjusted \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.982 (0.966-0.997) p = 0.019\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.845 (1.261-2.699) p = 0.002\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.223 (0.836-1.787) p = 0.300\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Model 1 \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.985 (0.969-1.001) p = 0.061\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.735 (1.180-2.551) p = 0.005\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.200 (0.816-1.766) p = 0.354\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Model 2 \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.990 (0.973-1.007) p = 0.239\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.568 (1.035-2.374) p = 0.034\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.191 (0.785-1.807) p = 0.410\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Conduit Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Conduit Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Conduit Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Conduit Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Conduit Strain}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Range}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.00 -- 79.94\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.00 -- 11.76\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11.79 -- 20.31\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20.33 -- 79.94\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Unadjusted \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.977 (0.962-0.991) p = 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.930 (1.319-2.825) p = 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.266 (0.866-1.852) p = 0.224\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Model 1 \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.979 (0.964-0.994) p = 0.006\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.873 (1.244-2.820) p = 0.003\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.250 (0.849-1.841) p = 0.259\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Model 2 \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.971 (0.955-0.988) p = 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.288 (1.448-3.613) p = 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.532 (1.007-2.333) p = 0.047\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Model 1: Adjusted for age and sex

Model 2: Adjusted for model 1 plus variables differing between the two
groups (SBP, NIHSS, and CHF)

\textbf{Table 3. LA Strain and AF detection in 307 ESUS patients}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{AF detected} (n = 39)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{No AF detected} (n = 268)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{p-value}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Left Atrial Reservoir Strain (mean \emph{+} SD)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
25.15 \selectlanguage{ngerman}± 13.57\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
32.95 \selectlanguage{ngerman}± 16.20\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.005\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Left Atrial Contractile Strain (mean \emph{+} SD)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
12.24 \selectlanguage{ngerman}± 10.00\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
15.95 \selectlanguage{ngerman}± 9.41\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.023\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Left Atrial Conduit Strain (mean \emph{+} SD)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
12.91 \selectlanguage{ngerman}± 6.45\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
17.00 \selectlanguage{ngerman}± 11.09\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.025\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

AF: Atrial Fibrillation

\textbf{Table 4. LA Strain in 32 ESUS patients found to have AF on
Cardiac Event Monitoring: Comparing AF Burden \textless{} 24 hours
versus AF Burden \emph{\textgreater{}} 24 hours}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{AF Burden \textless{} 24hr} (n = 24)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{AF Burden \emph{\textgreater{}} 24hr} (n = 8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{p-value}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Left Atrial Reservoir Strain (mean \emph{+} SD)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
26.15 \selectlanguage{ngerman}± 15.25\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
26.50 \selectlanguage{ngerman}± 12.17\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.953\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Left Atrial Contractile Strain (mean \emph{+} SD)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
12.79 \selectlanguage{ngerman}± 11.90\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
11.56 \selectlanguage{ngerman}± 6.74\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.785\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Left Atrial Conduit Strain (mean \emph{+} SD)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
13.36 \selectlanguage{ngerman}± 6.31\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
14.94 \selectlanguage{ngerman}± 7.12\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.557\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

AF: Atrial Fibrillation

\textbf{Table 5. Multivariable Analysis Showing Associations between LA
Reservoir, Contractile, and Conduit Strain and Atrial Fibrillation
Detection in 307 ESUS Patients}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Overall}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Tertile 1}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Tertile 2}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Tertile 3}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Reservoir Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Reservoir Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Reservoir Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Reservoir Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Reservoir Strain}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Range}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7.20 -- 103.78\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7.20 -- 25.48\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
25.60 -- 36.57\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
36.97 -- 103.78\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Unadjusted \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.957 (0.929-0.987) p = 0.005\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.534 (1.029-6.236) p = 0.043\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.240 (0.451-3.411) p = 0.677\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Model 1 \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.966 (0.938-0.995) p = 0.023\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.092 (0.836-5.237) p = 0.115\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.255 (0.451-3.495) p = 0.663\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Contractile Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Contractile Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Contractile Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Contractile Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Contractile Strain}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Range}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.58 -- 56.44\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.58 -- 11.18\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11.23 -- 18.08\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
18.27 -- 56.44\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Unadjusted \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.949 (0.907-0.993) p = 0.025\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.828 (1.158-6.903) p = 0.022\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.005 (0.349-2.894) p = 0.993\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Model 1 \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.954 (0.913-0.996) p = 0.033\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.797 (1.133-6.905) p = 0.026\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.245 (0.423-3.662) p = 0.691\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Conduit Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Conduit Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Conduit Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Conduit Strain}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{LA Conduit Strain}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Range}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.00 -- 79.94\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.00 -- 11.76\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11.82 -- 19.70\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20.54 -- 79.94\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Unadjusted \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.952 (0.912-0.994) p = 0.025\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.614 (1.003-6.815) p = 0.049\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.016 (0.731-5.557) p = 0.176\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Model 1 \textbf{OR (95\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.969 (0.928-1.011) p = 0.148\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.776 (0.657-4.806) p = 0.258\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.786 (0.639-4.995) p = 0.269\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Model 1: Adjusted for age

\textbf{Figure 1}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Flowchart of study population\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2}

\textbf{Panel (A):} Left atrial tracking. \textbf{Panel (B)} Left atrial
strain curve

\textbf{Figure 3: Central Illustration}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Panel (A)} illustrates the progression of left atrial
cardiopathy. Subtle changes in all three phases of left atrial strain in
the early stages of atrial cardiopathy precede more drastic changes in
left atrial volume and strain in advanced stages of atrial
cardiopathy.\textbf{Panel (B)} illustrates the pathophysiologic
consequences of atrial cardiopathy, including atrial fibrillation and
thromboembolism. Note that atrial fibrillation can be both a cause and a
result of atrial cardiopathy.

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

