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\begin{document}

\title{Effect of systolic dysfunction and elevated left ventricular end
diastolic pressure on 3-year clinical outcomes in patients with atrial
fibrillation}



\author[1]{YU HYEYON}%
\author[2]{JIHUN AHN}%
\affil[1]{School of Nursing, College of Medicine, Soonchunhyang University, Asan, Korea}%
\affil[2]{Konkuk University Chungju Hospital}%


\vspace{-1em}



  
  \date{June 17, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objectives: Systolic and diastolic dysfunctions are related to adverse
clinical outcomes in patients with sinus rhythm. The aim of this study
was to clarify the prognostic significance of systolic and diastolic
dysfunctions in patients with chronic persistent atrial fibrillation
(AF). Methods: We evaluated data for 114 consecutive patients with
chronic AF who underwent measurement of LVEDP at our hospital between 1
March 2011 and 31 December 2014. In total, 114 consecutive patients with
chronic AF were divided into two groups according to the left
ventricular ejection fraction (LVEF): LVEF \textless{} 50 (reduced
ejection fraction, REF group) and LVEF [?]50 (preserved EF, PEF group).
The PEF group was further divided into two subgroups according to the
left ventricular end-diastolic filling pressure (LVEDP): LVEDP
\textgreater{}15 mmHg and LVEDP [?] 15 mmHg. The 3-year clinical outcomes
were compared between the PEF and REF groups and the LVEDP [?]15 mmHg and
LVEDP \textless{}15 mmHg groups. Results: During the 3-year follow-up
period, the rate of heart failure (HF) hospitalisation and incidence of
AF with rapid ventricular rhythm (RVR) were higher in the REF group than
in the PEF group. Multivariate analysis revealed that REF was the only
significant predictor of HF hospitalisation (hazard ratio, 4.71; 95\%
confidence interval, 1.48--15.02; p=0.009). Conclusions: Our
observations during a mid-term follow-up period revealed that systolic
dysfunction could be an important predictor of HF hospitalisation in
patients with AF. However, elevated LVEDP may not be associated with
mid-term adverse clinical outcomes in patients without systolic
dysfunction.%
\end{abstract}%



\sloppy


\textbf{Effect of systolic dysfunction and elevated left ventricular end
diastolic pressure on 3-year clinical outcomes in patients with atrial
fibrillation}HyeYon Yu RN, PhD\textsuperscript{1}, JiHun Ahn MD,
PhD\textsuperscript{2}\textbf{Affiliations}:

\textsuperscript{1}School of Nursing, College of Medicine, Soonchunhyang
University, Asan, Korea

\textsuperscript{2}Department of Internal Medicine, Konkuk University
Chungju Hospital, Chungju, Korea

\textbf{Correspondence}

Ji Hun Ahn MD, PhD

Department of Internal Medicine, Konkuk University Chungju Hospital,
Chungju, Korea

82, Gugwon-daero, Chungju-si, Chungcheongbuk-do, Korea

Mobile.: +82-10-6285-5204

Fax: +82-43-840-8888

Email: jichoona@gmail.com

ORCID: https//orcid.org/0000-0003-1858-1803

\textbf{Short title:} Prognostic value of diastolic dysfunction in AF

\textbf{Funding statement}

This work was supported by the Soonchunhyang University Research Fund
(grant number 20170813).

\textbf{KEYWORDS}

Atrial fibrillation, heart failure, ejection fraction, left ventricular
end-diastolic filling pressure

\textbf{Conflicts of Interest}

The authors report no financial relationships or conflicts of interest
regarding the content herein.

\textbf{ABSTRACT}

\textbf{Objectives} : Systolic and diastolic dysfunctions are related to
adverse clinical outcomes in patients with sinus rhythm. The aim of this
study was to clarify the prognostic significance of systolic and
diastolic dysfunctions in patients with chronic persistent atrial
fibrillation (AF).

\textbf{Methods} : We evaluated data for 114 consecutive patients with
chronic AF who underwent measurement of LVEDP at our hospital between 1
March 2011 and 31 December 2014. In total, 114 consecutive patients with
chronic AF were divided into two groups according to the left
ventricular ejection fraction (LVEF): LVEF \textless{} 50 (reduced
ejection fraction, REF group) and LVEF [?]50 (preserved EF, PEF group).
The PEF group was further divided into two subgroups according to the
left ventricular end-diastolic filling pressure (LVEDP): LVEDP
\textgreater{}15 mmHg and LVEDP [?] 15 mmHg. The 3-year clinical outcomes
were compared between the PEF and REF groups and the LVEDP [?]15 mmHg and
LVEDP \textless{}15 mmHg groups.

\textbf{Results} : During the 3-year follow-up period, the rate of heart
failure (HF) hospitalisation and incidence of AF with rapid ventricular
rhythm (RVR) were higher in the REF group than in the PEF group.
Multivariate analysis revealed that REF was the only significant
predictor of HF hospitalisation (hazard ratio, 4.71; 95\% confidence
interval, 1.48--15.02; p=0.009).

\textbf{Conclusions} : Our observations during a mid-term follow-up
period revealed that systolic dysfunction could be an important
predictor of HF hospitalisation in patients with AF. However, elevated
LVEDP may not be associated with mid-term adverse clinical outcomes in
patients without systolic dysfunction.

\textbf{KEYWORDS}

Atrial fibrillation, heart failure, ejection fraction, left ventricular
end-diastolic filling pressure

\textbf{INTRODUCTION}

Atrial fibrillation (AF) is one of the most common forms of cardiac
arrhythmia that is associated with not only increased mortality but also
the progression of heart failure (HF) and an increased frequency of HF
hospitalisation.\textsuperscript{1 2} The incidence and prevalence of AF
are expected to double in the next 20 years, with corresponding
increases in the mortality rate and medical cost.\textsuperscript{3
4}Some risk factors such as old age and combined coronary artery disease
(CAD) are known predictors of adverse outcomes in patients with
AF.\textsuperscript{5} In the setting of sinus rhythm, both systolic and
diastolic dysfunctions are well-known risk factors of adverse outcomes
such as mortality and HF hospitalisation.\textsuperscript{6 7} However,
data regarding the relationship between diastolic dysfunction and
adverse cardiac events in patients with AF are insufficient. Moreover,
in the setting of chronic AF, prediction of the status of diastolic
function is exceedingly difficult.\textsuperscript{8} During progression
of diastolic dysfunction, elevated left ventricular end-diastolic
pressure (LVEDP) reflects the extent of diastolic
dysfunction.\textsuperscript{9 10} However, no studies have evaluated
the relationship between elevated LVEDP and adverse cardiac outcomes in
patients with chronic AF. Therefore, the aim of the present study was to
clarify the prognostic significance of systolic and diastolic
dysfunctions in patients with chronic persistent AF by evaluating the
relationship of systolic dysfunction as well as elevated LVEDP, which
can reflect the extent of diastolic dysfunction, with the 3-year
clinical outcomes.

METHODS

Study design and population

We evaluated data for 114 consecutive patients with chronic AF who
underwent measurement of LVEDP at our hospital between 1 March 2011 and
31 December 2014. All patients presented with symptoms such as
unexplained dyspnea, chest discomfort, and chest pain and underwent
coronary angiography after providing informed consent. We excluded
patients with paroxysmal AF, mitral stenosis, rheumatic disease, severe
mitral regurgitation, moderate to severe aortic stenosis, severe aortic
regurgitation, prosthetic valve disease and severe tricuspid
regurgitation, and/or right ventricular dysfunction. The included
patients were divided into two groups according to their left
ventricular ejection fraction (LVEF): LVEF \textless{} 50 (n = 24; REF
group) and LVEF [?] 50 (n = 90; PEF group). For evaluation of the outcomes
with regard to diastolic dysfunction, the PEF group was further divided
into two subgroups according to the left ventricular end-diastolic
filling pressure (LVEDP): LVEDP \textgreater{}15 mmHg (n = 38) and LVEDP
[?]15 mmHg (n = 52). Clinical data were obtained by face-to-face
interviews in the outpatient clinic and/or telephone interviews, a
complete review of electronic medical records, physical examinations,
history taking, laboratory examinations, echocardiography, and
haemodynamic measurements.

This single-centre study was performed at a university hospital, and the
protocol was approved by the institutional review (IRB) board of the
hospital (IRB approval number: 2015-14). All patients or their legal
guardians were provided a thorough written and verbal explanation of the
study procedures, following which they gave written consent for
participation in the study.

Echocardiography and haemodynamic measurements

A single experienced physician performed baseline transthoracic
echocardiography (TTE) with the patient in the left lateral decubitus
position within 24 h before the measurement of LVEDP using a GE Vivid 7
device equipped with M4S transducers (GE Medical, Milwaukee, USA). All
measured images were digitally recorded for subsequent analysis.
Measured echocardiographic parameters included the ejection fraction
(EF), left ventricular end-diastolic diameter (LVEDD), left ventricular
end-systolic diameter (LVESD), left atrial volume, degree of mitral and
aortic regurgitation, and stenosis. LVEF was calculated using the
biplane modified Simpson's method.\textsuperscript{11} Echocardiographic
Doppler parameters were also measured and stored. The transmitral flow,
mitral annular motion velocity, E-wave deceleration time (DT), and
propagation velocity (Vp) were recorded for five consecutive cardiac
cycles, and the results were averaged. LVEDP and the minimal LV filling
pressure were measured using a 5-Fr pigtail catheter positioned at the
left ventricle and aorta during coronary angiography. LVEDP was measured
at the Z-point, which is identified on the left ventricular pressure
traceas the point at which the slope of the ventricular pressure
upstroke changes, and averaged over 10 consecutive
beats.\textsuperscript{12} An investigator blinded to the
echocardiographic data acquired the pressure values.

Clinical outcomes

The 3-year clinical outcomes were evaluated and compared between the REF
and PEF groups andthe two LVEDP groups. Clinical outcomes, including the
mortality rate; incidences of stroke, AF with rapid ventricular rhythm
(RVR), and bleeding; and rate of HF hospitalisation, were recorded for
all patients. RVR was defined as a ventricular response of
\textgreater{}100 beats/min at presentation. Bleeding referred to major
bleeding that was fatal or intracranial or affected another critical
anatomical site, or overt bleeding causing a decrease in haemoglobin of
[?]20 g/L or necessitating transfusion of [?]2 units of erythrocytes.

Data analyses

Intergroup differences in continuous variables, presented as means \selectlanguage{ngerman}±
standard deviations, were evaluated by Student's t-test. Differences in
categorical variables, expressed as numbers and percentages,were
analysed using the \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2}test or Fisher's exact test as
appropriate. Kaplan--Meier curves were generated for determination of
the time-dependent HF hospitalisation rate, with comparisons performed
using the log-rank test. Cox proportional hazards models were used to
estimate the risk factors for HF hospitalisation during the 3-year
period, with calculation of hazard ratios (HRs) and 95\% confidence
intervals (95\% CIs). A two-sided p-value of \textless{}0.05 was
considered statistically significant in all tests. All statistical
analyses were performed using SPSS 20 (IBM SPSS., Chicago, IL, USA).

RESULTS

\textbf{Descriptive clinical characteristics of the participants}

The baseline clinical characteristics of the 114 patients enrolled in
this studyare presented in Table 1. The REF and PEF groups showed no
significant differences in terms of sex, age, the prevalence of
hypertension and diabetes mellitus, a history of myocardial infarction
(MI), and the presence of CAD (Table 1). Baseline laboratory,
haemodynamic, and echocardiographic data for all patients are presented
in Table 1. There were no significant differences in laboratory and
haemodynamic data, including LVEDP, between the REF and PEF groups.
However, EF during the index admission was 37.8\% \selectlanguage{ngerman}± 9.2\% in the REF
group and 60.9\% ± 5.2\% in the PEF group, with a significant difference
between groups (p\textless{}0.01). With regard to echocardiographic
parameters of diastolic function,EF, E/e', and E/Vp (p\textless{}0.01
for all) were significantly worse in the REF group than in the PEF
group, whereas the left atrial volume index (LAVI)showed no significant
difference between groups (Table 1). With regard to the baseline
clinical characteristics of patients in the two LVEDP subgroups in the
PEF group, no significant differences were observed in terms of sex,
age, the prevalence of hypertension and diabetes mellitus, a history of
MI, and the presence of CAD (Table 2). Baseline laboratory,
haemodynamic, and echocardiographic data for the LVEDP \textgreater{} 15
mmHg and LVEDP \selectlanguage{english}[?] 15 mmHg subgroups are shown in Table 2. LAVI, E/e,' and
E/Vp were significantly worse in the former group than in the latter
group (p\textless{}0.01 for all).

\textbf{Clinical outcomes of the participants according to LVEF}

The 3-year clinical outcomes of all patients (REF vs. PEF groups) are
presented in Table 3. The mortality rate and the incidences of stroke
and bleeding were not significantly different between the two groups.
Two patients died during the observation period; the causes were hepatic
encephalopathy with liver cirrhosis and newly diagnosed terminal cancer
in the REF and PEF groups, respectively. However, the rate of HF
hospitalisation (29.2\% vs 8.9\%, p \textless{} 0.02) and incidence of
AF with RVR (20.8\% vs 3.3\%, p \textless{} 0.01) were significantly
higher in the REF group than in the PEF group. Time-dependent
Kaplan-Meier analyses and log-rank tests revealed a high rate of HF
hospitalisation in the REF group (Fig 1a). Cox proportional hazards
models with univariate and multivariateanalyses found that reduced LVEF
(\textless{}50\%) was an important independent predictor of HF
hospitalisation (Table 4).

\textbf{Clinical outcomes of the participants according to LVEDP}

The 3-year clinical outcomes of patients in the LVEDP \textgreater{}15
mmHg and LVEDP \selectlanguage{english}[?]15 mmHg groups are presented in Table 5. There were no
significant differences between the two groups. Although the rate of HF
hospitalisation tended to be higher in the LVEDP \textgreater{}15 mmHg
group, the difference was not statistically significant (15.4\% vs
21.1\%, p = 0.58). Time-dependent Kaplan--Meier analyses and log-rank
tests showed no difference in the rate of HF hospitalisation between the
two groups (Fig 1b).

DISSCUSSION

In the present study, we evaluated the relationship of systolic
dysfunction as well as the level of LVEDP with the 3-year clinical
outcomes in patients with chronic AF. The main results of our study were
as follows. First, systolic dysfunction was related with adverse
outcomes such as heart failure (HF) hospitalisation and the occurrence
of AF with rapid ventricular rhythm during the 3-year observation
period. In addition, systolic dysfunction (LVEDP \textless{} 50\%) was
an important independent predictor of HF hospitalisation. Second,
elevated LVEDP, which is the key finding in patients with diastolic
dysfunction, was not associated with mid-term adverse outcomes. To our
knowledge, this is the first study to assess the effect of increased
LVEDP on mid-term outcomes in patients with chronic AF. These results
highlight the importance of paying more attention to a low EF detected
by echocardiography than to diastolic parameters in patients with
chronic AF.

AF is one of the most common forms of cardiac arrhythmia requiring
treatment, and it is associated with increased rates of mortality and
hospitalisation.\textsuperscript{1 4} Some previous studies of patients
with AF also showed that patients with systolic dysfunction more
frequently exhibit all-cause mortality than do patients with a preserved
EF.\textsuperscript{13-15.} In a previous study, AF was theoretically
associated with the development of rapid rhythm, loss of atrial
contractility, and left atrial enlargement. These changes can lead to
left ventricular wall thickening, neurohormonal changes, and systolic
dysfunction, which is an important predictor of adverse cardiac
outcomes.\textsuperscript{5 16} However, in the present study, the
mortality rates for patients with REF and those with PEF were
comparable; this was probably because of the relatively short
observation period, small number of patients in the REF group, and event
rates. Although many studies have demonstrated a high mortality rate and
increased HF hospitalisation in patients with AF and reduced LVEF, a few
studies showed that reduced LVEF did not increase the HF hospitalisation
or stroke rate for patients with AF and HF, relative to the rates for
patients with AF and diastolic dysfunction.\textsuperscript{17 18} In
the present study, the HF hospitalisation rate was significantly higher
in the REF group than in the PEF group, with the rate being as high as
29.2\% in the former group. These findings could be carefully explained
by the relatively old age of the enrolled patients and the presence of
chronic persistent AF in all patients (patients with paroxysmal AF were
excluded).

Notably, the prognostic utility of LVEF measurements for patients with
AF is well established. However, in a very recent study, the authors
compared the long-term prognostic implications of AF and sinus rhythm in
patients with acute or chronic HF stratified according to the level of
LVEF and found that AF was not associated with worse cardiovascular
outcomes in patients with reduced LVEF.\textsuperscript{19} These varied
results could be caused by the complexity of AF. Therefore, prediction
of our results was difficult, and we carefully estimated that elevated
LVEDP would be related with adverse clinical outcomes. Studies that
investigated the relationship between LVEDP and clinical outcomes are
very limited because of the invasiveness of measurement methods.
Previously, some investigators reported that elevated LVEDP is an
important risk factor for adverse clinical outcomes in patients with
acute myocardial infarction.\textsuperscript{20-22} To our knowledge,
however, no study has evaluated the association between LVEDP and
clinical outcomes in patients with chronic AF. Only left ventricular
diastolic dysfunction (LVDD), measured by non-invasive tests such as
echocardiography, was proven to be correlated with adverse clinical
events such as hospitalisation and
stroke.\textsuperscript{23-25}However, in the setting of AF, atrial
contractile a synchronicity complicates the assessment of LVDD using
classic echocardiographic parameters.\textsuperscript{26 27} The
physiological hallmarks of LVDD are impaired relaxation and reduced
diastolic compliance, which increase the LV filling pressure.
\textsuperscript{28 29} Among patients with normal systolic function,
elevated LVEDP could represent early diastolic dysfunction or could be
the main physiological consequence of diastolic
dysfunction.\textsuperscript{30} We not only determined the relationship
between LVEDP and clinical outcomes in patients with chronic AF and a
preserved EF but also clarified the relationship between diastolic
dysfunction and adverse clinical outcomes such as mortality, stroke, and
HF hospitalisation. We found that echocardiographic parameters that
represent diastolic function, such as E/e' and E/Vp, were worse in the
LVEDP\textgreater{} 15 mmHg group. However, during the 3-year
observation period, no significant differences were found in terms of
adverse clinical outcomes between the LVEDP \textgreater{} 15 mmHg and
LVEDP \selectlanguage{english}[?] 15 mmHg groups. We speculate that chronic persistent AF leads to
irreversible, chronic structural and neurohormonal changes that could
affect both LVEDP and the clinical outcomes.

This study has some limitations, the main one being the retrospective
design without randomization. The number of patients was small and the
follow-up period relatively short. Because it was a single-center study,
it was difficult to collect an adequate number of patients with LV
pressure wave data and recruit a relatively homogenous group with
chronic persistent AF without valvular heart disease. Long-term clinical
follow-up will be necessary after recruitment of more patients,
particularly those with reduced LVEF. Even if we performed coronary
angiography on the basis of its broad indications, LVEDP measurements
were recorded for selective patients with symptoms such as unexplained
chest discomfort, unexplained broad-spectrum dyspnoea, and typical and
atypical chest pain. Further studies with long-term follow-up periods
are necessary after the recruitment of more patients for clarification
of the relationship between diastolic dysfunction or elevated LVEDP and
clinical outcomes. Furthermore, the number of patients treated with oral
anticoagulants was very low in our study, primarily because our hospital
is located in a rural area and the insurance system in Korea did not
cover treatment with direct oral anticoagulants during the study period.
Thus, the level of education and medical compliance were low, and the
patients frequently refused warfarin treatment because of the
inconvenience of blood sampling. Finally, LVEDP is affected by multiple
factors such as dehydration and volume overload (e.g. combination of
chronic kidney disease and anaemia), and elevated LVEDP cannot represent
diastolic dysfunction, particularly in the setting of chronic AF.

CONCLUSION

Despite the study limitations, the findings are clinically meaningful
because we investigated, for the first time, the relationship between
elevated LVEDP and mid-term clinical outcomes along with the
relationship between systolic dysfunction and clinical outcomes in
patients with chronic AF. Also, this study proved that diastolic
dysfunction itself does not appear to be a prognostic factor for
hospitalization due to heart failure. Clinicians should apply these
results during the treatment of patients with chronic AF, with careful
evaluation of systolic function and prevention of risk factors that lead
to LV systolic dysfunction.

CONTRIBUTORS

JH AHN conceptualized the study. JH AHN and HY YU cleansed the data. JH
AHN and HY YU analyzed the data. JH AHN and HY YU reviewed the data
analysis. JH AHN and HY YU wrote initial draft. JH AHN and HY YU
reviewed the manuscript and interpreted the findings.

COMPETING INTERESTS

None declared

\textbf{ETHIC APPROVAL}

This study protocol was approved by the institutional review (IRB) board
of the Soonchunhyang university hospital (IRB approval number: 2015-14).

\textbf{DATA AVAILABILITY STATEMENT}

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

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  1248-52.
\item
  Sohn DW, Song JM, Zo JH, \emph{et al} . Mitral annulus velocity in the
  evaluation of left ventricular diastolic function in atrial
  fibrillation. \emph{J Am Soc Echocardiogr} 1999;12: 927-31.
\item
  Al-Omari MA, Finstuen J, Appleton CP, \emph{et al} . Echocardiographic
  assessment of left ventricular diastolic function and filling pressure
  in atrial fibrillation.\emph{Am J Cardiol} 2008;101: 1759-65.
\item
  Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure--abnormalities
  in active relaxation and passive stiffness of the left ventricle.
  \emph{N Engl J Med} 2004;350: 1953-9.
\item
  Flachskampf FA, Biering-Sorensen T, Solomon SD, \emph{et al} . Cardiac
  imaging to evaluate left ventricular diastolic function. \emph{JACC
  Cardiovasc Imaging} 2015;8: 1071-93.
\item
  Paulus WJ, Tschope C, Sanderson JE,\emph{et al} . How to diagnose
  diastolic heart failure: A consensus statement on the diagnosis of
  heart failure with normal left ventricular ejection fraction by the
  heart failure and echocardiography associations of the european
  society of cardiology.\emph{Eur Heart J} 2007;28: 2539-50.
\end{enumerate}

\textbf{TABLE 1} Baseline clinical characteristics and Baseline
laboratory, haemodynamic, and echocardiographic data of patients with
chronic atrial fibrillation\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Characteristic & REF group (n = 24) & PEF group (n = 90) &
\emph{p}\tabularnewline
\midrule
\endhead
Age, years (mean \selectlanguage{ngerman}± standard deviation) & 69.13 \selectlanguage{ngerman}± 10.7 & 69.11 \selectlanguage{ngerman}± 10.3 &
0.99\tabularnewline
Sex, male; n (\%) & 15 (62.5) & 48 (53.3) & 0.42\tabularnewline
Smokers, n (\%) & 8 (33.3) & 24 (26.7) & 0.52\tabularnewline
NYHA class, n (\%) & & & 0.10\tabularnewline
Class 1 & 7 (29.2) & 38 (46.9) &\tabularnewline
Class 2 & 9 (37.5) & 25 (30.9) &\tabularnewline
Class 3 & 4 (16.7) & 15 (18.5) &\tabularnewline
Class 4 & 4 (16.7) & 3 (3.7) &\tabularnewline
Diabetes mellitus, n (\%) & 4 (16.7) & 23 (25.6) & 0.36\tabularnewline
Hypertension, n (\%) & 9 (37.5) & 50 (55.6) & 0.12\tabularnewline
Myocardial infarction, n (\%) & 4 (16.7) & 6 (6.7) & 0.21\tabularnewline
Hypercholesterolemia, n (\%) & 18 (75) & 44 (50) & 0.03\tabularnewline
Coronary artery disease, n (\%) & 10 (41.7) & 25 (28.1) &
0.20\tabularnewline
Aspirin, n (\%) & 16 (66.7) & 46 (51.1) & 0.17\tabularnewline
Clopidogrel, n (\%) & 7 (29.2) & 23 (25.6) & 0.72\tabularnewline
Warfarin, n (\%) & 13 (54.2) & 54 (60.0) & 0.61\tabularnewline
Angiotensin-converting enzyme inhibitor, n (\%) & 2 (8.3) & 3 (3.4) &
0.29\tabularnewline
Angiotensin receptor blocker, n (\%) & 12 (50.0) & 33 (36.7) &
0.24\tabularnewline
Diuretics, n (\%) & 17 (70.8) & 47 (52.2) & 0.10\tabularnewline
Digitalis, n (\%) & 12 (50.0) & 36 (40.0) & 0.38\tabularnewline
Beta-blocker, n (\%) & 15 (62.5) & 49 (54.4) & 0.48\tabularnewline
Calcium channel blocker, n (\%) & 10 (41.7) & 33 (36.7) &
0.65\tabularnewline
Heart rate (beats/minute) & 89.0 \selectlanguage{ngerman}± 22.1 & 82.7 \selectlanguage{ngerman}± 22.8 &
0.23\tabularnewline
Systolic blood pressure (mmHg) & 122.8 \selectlanguage{ngerman}± 21.0 & 123.4 \selectlanguage{ngerman}± 18.6 &
0.90\tabularnewline
Diastolic blood pressure (mmHg) & 76.4 \selectlanguage{ngerman}± 12.4 & 76.8 \selectlanguage{ngerman}± 12.4 &
0.90\tabularnewline
CHA\textsubscript{2}DS\textsubscript{2}-VASc score & 2.18 \selectlanguage{ngerman}± 0.15 & 2.35
\selectlanguage{ngerman}± 0.11 & 0.12\tabularnewline
High-sensitivity CRP level (mg/dl) & 1.0 \selectlanguage{ngerman}± 1.4 & 1.0 \selectlanguage{ngerman}± 2.3 &
0.96\tabularnewline
Creatinine level (mg/dl) & 1.2 \selectlanguage{ngerman}± 1.1 & 1.1 \selectlanguage{ngerman}± 1.0 & 0.30\tabularnewline
BNP level (pg/ml) & 1170.3 \selectlanguage{ngerman}± 393.0 & 393.0 \selectlanguage{ngerman}± 547.0 &
0.04*\tabularnewline
Minimal left ventricular pressure (mmHg) & 12.0 \selectlanguage{ngerman}± 5.0 & 10.5 \selectlanguage{ngerman}± 4.7 &
0.17\tabularnewline
LVEDP (mmHg) & 17.3 \selectlanguage{ngerman}± 7.9 & 14.9 \selectlanguage{ngerman}± 4.6 & 0.17\tabularnewline
Echocardiographic data & & &\tabularnewline
EF (\%) & 37.8 \selectlanguage{ngerman}± 9.2 & 60.9 \selectlanguage{ngerman}± 5.2 & \textless{}0.01**\tabularnewline
E & 92.6 \selectlanguage{ngerman}± 21.1 & 95.0 \selectlanguage{ngerman}± 24.6 & 0.67\tabularnewline
DT (m/sec) & 151.1 \selectlanguage{ngerman}± 41.2 & 167.9 \selectlanguage{ngerman}± 33.9 & 0.04*\tabularnewline
e' & 5.4 \selectlanguage{ngerman}± 1.5 & 7.0 \selectlanguage{ngerman}± 1.9 & \textless{}0.01**\tabularnewline
E/e' & 18.3 \selectlanguage{ngerman}± 5.8 & 14.3 \selectlanguage{ngerman}± 5.4 & \textless{}0.01**\tabularnewline
Vp (m/s) & 39.3 \selectlanguage{ngerman}± 7.8 & 58.2 \selectlanguage{ngerman}± 15.7 & \textless{}0.01**\tabularnewline
E/Vp & 2.4 \selectlanguage{ngerman}± 0.4 & 1.8 \selectlanguage{ngerman}± 0.8 & \textless{}0.01**\tabularnewline
LAVI (ml/m\textsuperscript{2}) & 49.0 \selectlanguage{ngerman}± 24.1 & 43.2 \selectlanguage{ngerman}± 16.9 &
0.18\tabularnewline
LVMI (gm/m\textsuperscript{2}) & 125.2 \selectlanguage{ngerman}± 49.8 & 96.2 \selectlanguage{ngerman}± 28.9 &
0.01*\tabularnewline
RWT & 0.3 \selectlanguage{ngerman}± 0.1 & 0.3 \selectlanguage{ngerman}± 0.1 & 0.39\tabularnewline
PAP (mmHg) & 39.2 \selectlanguage{ngerman}± 14.1 & 34.0 \selectlanguage{ngerman}± 11.1 & 0.11\tabularnewline
LVEDD (mm) & 56.9 \selectlanguage{ngerman}± 7.7 & 51.2 \selectlanguage{ngerman}± 5.0 & \textless{}0.01**\tabularnewline
LVESD (mm) & 46.5 \selectlanguage{ngerman}± 8.1 & 34.4 \selectlanguage{ngerman}± 4.3 & \textless{}0.01**\tabularnewline
IVS (mm) & 9.1 \selectlanguage{ngerman}± 2.1 & 8.6 \selectlanguage{ngerman}± 2.0 & 0.29\tabularnewline
LVPW (mm) & 8.7 \selectlanguage{ngerman}± 2.2 & 8.6 \selectlanguage{ngerman}± 1.5 & 0.73\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: REF=reduced ejection fraction (ejection fraction
\textless{} 50\%); PEF=preserved ejection fraction (ejection fraction [?]
50\%), NYHA=New York Heart Association; CRP=C-reactive protein;
BNP=brain natriuretic peptide; LVEDP=left ventricular end-diastolic
filling pressure; EF=ejection fraction; DT=deceleration time; E=early
diastolic mitral inflow; e'= early diastolic mitral annular tissue
velocity; Vp=propagation velocity; LAVI= left atrial volume index;
LVMI=left ventricular mass index; RWT=relative wall thickness;
PAP=pulmonary arterial systolic pressure; LVEDD=left ventricular
end-diastolic diameter; LVESD=left ventricular end-systolic diameter;
IVS=interventricular septum; LVPW=left ventricular posterior free wall.

* p\textless{}0.05; **p\textless{}0.01

\textbf{TABLE 2} Baseline clinical characteristics and Baseline
laboratory, haemodynamic, and echocardiographic data of patients with
chronic atrial fibrillation and a preserved ejection fraction\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
Characteristics & Characteristics & LVEDP [?] 15 mmHg group (n = 52) &
LVEDP [?] 15 mmHg group (n = 52) & LVEDP \textgreater{} 15 mmHg group (n =
38) & LVEDP \textgreater{} 15 mmHg group (n = 38) & \emph{p} &
\emph{p}\tabularnewline
\midrule
\endhead
Age, years (mean \selectlanguage{ngerman}± standard deviation) & Age, years (mean \selectlanguage{ngerman}± standard
deviation) & 69.6 \selectlanguage{ngerman}± 9.5 & 69.6 \selectlanguage{ngerman}± 9.5 & 68.5 \selectlanguage{ngerman}± 11.3 & 68.5 \selectlanguage{ngerman}± 11.3 & 0.62
& 0.62\tabularnewline
Sex, male; n (\%) & Sex, male; n (\%) & 33 (63.5) & 33 (63.5) & 15
(39.5) & 15 (39.5) & 0.02* & 0.02*\tabularnewline
Smokers, n (\%) & Smokers, n (\%) & 13 (25.0) & 13 (25.0) & 11 (28.9) &
11 (28.9) & 0.68 & 0.68\tabularnewline
NYHA class, n (\%) & NYHA class, n (\%) & & & & & &\tabularnewline
Class 1 & Class 1 & 22 (46.8) & 22 (46.8) & 16 (47.1) & 16 (47.1) & 0.46
& 0.46\tabularnewline
Class 2 & Class 2 & 13 (27.7) & 13 (27.7) & 12 (35.3) & 12 (35.3) &
&\tabularnewline
Class 3 & Class 3 & 9 (19.1) & 9 (19.1) & 6 (17.6) & 6 (17.6) &
&\tabularnewline
Class 4 & Class 4 & 3 (6.4) & 3 (6.4) & 0 (0.0) & 0 (0.0) &
&\tabularnewline
Diabetes mellitus, n (\%) & Diabetes mellitus, n (\%) & 14 (26.9) & 14
(26.9) & 9 (23.7) & 9 (23.7) & 0.73 & 0.73\tabularnewline
Hypertension, n (\%) & Hypertension, n (\%) & 26 (50.0) & 26 (50.0) & 24
(63.2) & 24 (63.2) & 0.22 & 0.22\tabularnewline
Myocardial infarction, n (\%) & Myocardial infarction, n (\%) & 3 (5.8)
& 3 (5.8) & 3 (7.9) & 3 (7.9) & 0.69 & 0.69\tabularnewline
Hypercholesterolemia, n (\%) & Hypercholesterolemia, n (\%) & 26 (51.0)
& 26 (51.0) & 18 (48.6) & 18 (48.6) & 0.83 & 0.83\tabularnewline
Coronary artery disease, n (\%) & Coronary artery disease, n (\%) & 15
(29.4) & 15 (29.4) & 10 (26.3) & 10 (26.3) & 0.75 & 0.75\tabularnewline
Aspirin, n (\%) & Aspirin, n (\%) & 26 (50.0) & 26 (50.0) & 20 (52.6) &
20 (52.6) & 0.81 & 0.81\tabularnewline
Clopidogrel, n (\%) & Clopidogrel, n (\%) & 9 (17.3) & 9 (17.3) & 14
(36.8) & 14 (36.8) & 0.04* & 0.04*\tabularnewline
Warfarin, n (\%) & Warfarin, n (\%) & 35 (67.3) & 35 (67.3) & 19 (50.0)
& 19 (50.0) & 0.10 & 0.10\tabularnewline
Angiotensin-converting enzyme inhibitor, n (\%) & Angiotensin-converting
enzyme inhibitor, n (\%) & 1 (1.9) & 1 (1.9) & 2 (5.4) & 2 (5.4) & 0.57
& 0.57\tabularnewline
Angiotensin receptor blocker, n (\%) & Angiotensin receptor blocker, n
(\%) & 15 (28.8) & 15 (28.8) & 18 (47.4) & 18 (47.4) & 0.07 &
0.07\tabularnewline
Diuretics, n (\%) & Diuretics, n (\%) & 26 (50.0) & 26 (50.0) & 21
(55.3) & 21 (55.3) & 0.62 & 0.62\tabularnewline
Digitalis, n (\%) & Digitalis, n (\%) & 22 (42.3) & 22 (42.3) & 14
(36.8) & 14 (36.8) & 0.60 & 0.60\tabularnewline
Beta-blocker, n (\%) & Beta-blocker, n (\%) & 28 (53.8) & 28 (53.8) & 21
(55.3) & 21 (55.3) & 0.89 & 0.89\tabularnewline
Calcium channel blocker, n (\%) & Calcium channel blocker, n (\%) & 22
(42.3) & 22 (42.3) & 11 (28.9) & 11 (28.9) & 0.19 & 0.19\tabularnewline
Heart rate (beats/minute) & 82.5 \selectlanguage{ngerman}± 18.5 & 82.5 \selectlanguage{ngerman}± 18.5 & 82.9 \selectlanguage{ngerman}± 28.0 &
82.9 \selectlanguage{ngerman}± 28.0 & 0.95 & 0.95 &\tabularnewline
Systolic blood pressure (mmHg) & 125.2 \selectlanguage{ngerman}± 18.9 & 125.2 \selectlanguage{ngerman}± 18.9 & 120.9 \selectlanguage{ngerman}±
18.3 & 120.9 \selectlanguage{ngerman}± 18.3 & 0.28 & 0.28 &\tabularnewline
Diastolic blood pressure (mmHg) & 78.1 \selectlanguage{ngerman}± 11.9 & 78.1 \selectlanguage{ngerman}± 11.9 & 75.0 \selectlanguage{ngerman}±
12.9 & 75.0 \selectlanguage{ngerman}± 12.9 & 0.23 & 0.23 &\tabularnewline
CHA\textsubscript{2}DS-VASc score & 2.38 \selectlanguage{ngerman}± 0.11 & 2.38 \selectlanguage{ngerman}± 0.11 & 2.33 \selectlanguage{ngerman}±
0.13 & 2.33 \selectlanguage{ngerman}± 0.13 & 0.11 & 0.11 &\tabularnewline
High-sensitivity CRP level (mg/dl) & 0.7 \selectlanguage{ngerman}± 1.6 & 0.7 \selectlanguage{ngerman}± 1.6 & 1.3 \selectlanguage{ngerman}± 3.1 &
1.3 \selectlanguage{ngerman}± 3.1 & 0.25 & 0.25 &\tabularnewline
Creatinine level (mg/dl) & 1.0 \selectlanguage{ngerman}± 0.9 & 1.0 \selectlanguage{ngerman}± 0.9 & 1.1 \selectlanguage{ngerman}± 1.0 & 1.1 \selectlanguage{ngerman}± 1.0
& 0.30 & 0.30 &\tabularnewline
BNP level (pg/ml) & 380.9 \selectlanguage{ngerman}± 676.9 & 380.9 \selectlanguage{ngerman}± 676.9 & 409.4 \selectlanguage{ngerman}± 301.6 &
409.4 \selectlanguage{ngerman}± 301.6 & 0.82 & 0.82 &\tabularnewline
Minimal left ventricular pressure (mmHg) & 8.0 \selectlanguage{ngerman}± 2.7 & 8.0 \selectlanguage{ngerman}± 2.7 & 13.9
\selectlanguage{ngerman}± 4.9 & 13.9 \selectlanguage{ngerman}± 4.9 & \textless{}0.01** & \textless{}0.01**
&\tabularnewline
LVEDP (mmHg) & 11.7 \selectlanguage{ngerman}± 2.4 & 11.7 \selectlanguage{ngerman}± 2.4 & 19.2 \selectlanguage{ngerman}± 3.1 & 19.2 \selectlanguage{ngerman}± 3.1 &
\textless{}0.01** & \textless{}0.01** &\tabularnewline
Echocardiographic findings & & & & & & &\tabularnewline
EF (\%) & 61.4 \selectlanguage{ngerman}± 4.5 & 61.4 \selectlanguage{ngerman}± 4.5 & 60.2 \selectlanguage{ngerman}± 6.1 & 60.2 \selectlanguage{ngerman}± 6.1 & 0.30 &
0.30 &\tabularnewline
E & 86.4 \selectlanguage{ngerman}± 18.6 & 86.4 \selectlanguage{ngerman}± 18.6 & 106.5 \selectlanguage{ngerman}± 27.1 & 106.5 \selectlanguage{ngerman}± 27.1 &
\textless{}0.01** & \textless{}0.01** &\tabularnewline
DT (m/sec) & 169.8 \selectlanguage{ngerman}± 32.4 & 169.8 \selectlanguage{ngerman}± 32.4 & 165.3 \selectlanguage{ngerman}± 36.2 & 165.3 \selectlanguage{ngerman}± 36.2 &
0.54 & 0.54 &\tabularnewline
e' & 7.3 \selectlanguage{ngerman}± 2.2 & 7.3 \selectlanguage{ngerman}± 2.2 & 6.7 \selectlanguage{ngerman}± 1.5 & 6.7 \selectlanguage{ngerman}± 1.5 & 0.18 & 0.18
&\tabularnewline
E/e' & 12.5 \selectlanguage{ngerman}± 4.5 & 12.5 \selectlanguage{ngerman}± 4.5 & 16.6 \selectlanguage{ngerman}± 5.6 & 16.6 \selectlanguage{ngerman}± 5.6 &
\textless{}0.01** & \textless{}0.01** &\tabularnewline
Vp (m/s) & 62.2 \selectlanguage{ngerman}± 15.5 & 62.2 \selectlanguage{ngerman}± 15.5 & 52.5 \selectlanguage{ngerman}± 14.6 & 52.5 \selectlanguage{ngerman}± 14.6 & 0.20
& 0.20 &\tabularnewline
E/Vp & 1.5 \selectlanguage{ngerman}± 0.05 & 1.5 \selectlanguage{ngerman}± 0.05 & 2.3 \selectlanguage{ngerman}± 0.9 & 2.3 \selectlanguage{ngerman}± 0.9 &
\textless{}0.01** & \textless{}0.01** &\tabularnewline
LAVI (ml/m\textsuperscript{2}) & 38.3 \selectlanguage{ngerman}± 12.0 & 38.3 \selectlanguage{ngerman}± 12.0 & 49.8 \selectlanguage{ngerman}± 20.2
& 49.8 \selectlanguage{ngerman}± 20.2 & \textless{}0.01** & \textless{}0.01** &\tabularnewline
LVMI (gm/m\textsuperscript{2}) & 92.0 \selectlanguage{ngerman}± 25.5 & 92.0 \selectlanguage{ngerman}± 25.5 & 101.7 \selectlanguage{ngerman}±
32.3 & 101.7 \selectlanguage{ngerman}± 32.3 & 0.12 & 0.12 &\tabularnewline
RWT & 0.3 \selectlanguage{ngerman}± 0.1 & 0.3 \selectlanguage{ngerman}± 0.1 & 0.3 \selectlanguage{ngerman}± 0.1 & 0.3 \selectlanguage{ngerman}± 0.1 & 0.82 & 0.82
&\tabularnewline
PAP (mmHg) & 31.6 \selectlanguage{ngerman}± 9.2 & 31.6 \selectlanguage{ngerman}± 9.2 & 37.2 \selectlanguage{ngerman}± 12.5 & 37.2 \selectlanguage{ngerman}± 12.5 & 0.02*
& 0.02* &\tabularnewline
LVEDD (mm) & 50.4 \selectlanguage{ngerman}± 4.6 & 50.4 \selectlanguage{ngerman}± 4.6 & 52.3 \selectlanguage{ngerman}± 5.2 & 52.3 \selectlanguage{ngerman}± 5.2 & 0.07 &
0.07 &\tabularnewline
LVESD (mm) & 33.7 \selectlanguage{ngerman}± 3.6 & 33.7 \selectlanguage{ngerman}± 3.6 & 35.4 \selectlanguage{ngerman}± 4.9 & 35.4 \selectlanguage{ngerman}± 4.9 & 0.06 &
0.06 &\tabularnewline
IVS (mm) & 8.6 \selectlanguage{ngerman}± 1.8 & 8.6 \selectlanguage{ngerman}± 1.8 & 8.7 \selectlanguage{ngerman}± 2.2 & 8.7 \selectlanguage{ngerman}± 2.2 & 0.93 & 0.93
&\tabularnewline
LVPW (mm) & 8.4 \selectlanguage{ngerman}± 1.2 & 8.4 \selectlanguage{ngerman}± 1.2 & 8.7 \selectlanguage{ngerman}± 1.8 & 8.7 \selectlanguage{ngerman}± 1.8 & 0.31 & 0.31
&\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: LVEDP=left ventricular end-diastolic filling pressure;
NYHA=New York Heart Association

CRP=C-reactive protein; BNP=brain natriuretic peptide; LVEDP=left
ventricular end-diastolic filling pressure; EF=ejection fraction;
DT=deceleration time; E=early diastolic mitral inflow; e'=early
diastolic mitral annular tissue velocity; Vp=propagation velocity;
LAVI=left atrial volume index; LVMI=left ventricular mass index;
RWT=relative wall thickness; PAP=pulmonary arterial systolic pressure;
LVEDD=left ventricular end-diastolic diameter; LVESD=left ventricular
end-systolic diameter; IVS=interventricular septum; LVPW=left
ventricular posterior free wall.

* p\textless{}0.05; **p\textless{}0.01

\textbf{TABLE 3} Three-year clinical outcomes of patients with chronic
atrial fibrillation\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Characteristics & REF group (n = 24) & PEF group (n = 90) &
\emph{p}\tabularnewline
\midrule
\endhead
All-cause mortality, n (\%) & 1 (4.2) & 1 (1.1) & 0.38\tabularnewline
Stroke, n (\%) & 0 (0.0) & 3 (3.3) & 0.49\tabularnewline
Hospitalisation, n (\%) & 7 (29.2) & 16 (17.8) & 0.25\tabularnewline
AF with RVR, n (\%) & 5 (20.8) & 3 (3.3) & 0.01*\tabularnewline
Major bleeding, n (\%) & 1 (4.2) & 2 (2.2) & 0.51\tabularnewline
HF hospitalisation, n (\%) & 7 (29.2) & 8 (8.9) & 0.02*\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: AF=atrial fibrillation; RVR=rapid ventricular rhythm;
HF=heart failure

* p\textless{}0.05

\textbf{TABLE 4} Predictors of 3-year clinical outcomes for patients
with chronic atrial fibrillation\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Characteristics & Unadjusted (univariate analysis) & Unadjusted
(univariate analysis) & Unadjusted (univariate analysis) & Adjusted
(multivariate analysis) & Adjusted (multivariate analysis) & Adjusted
(multivariate analysis)\tabularnewline
\midrule
\endhead
& \textbf{HR} & \textbf{95\% CI} & p & \textbf{HR} & \textbf{95\% CI} &
p\tabularnewline
Age & 0.975 & 0.931--1.012 & 0.286 & 0.973 & 0.925--1.023 &
0.286\tabularnewline
Diabetes mellitus & 1.685 & 0.576--4.930 & 0.341 & 0.487 & 0.138--1.721
& 0.264\tabularnewline
BNP level & 1.000 & 1.000--1.000 & 0.185 & 1.000 & 1.000--1.000 &
0.908\tabularnewline
Hypertension & 0.817 & 0.296--2.253 & 0.696 & 1.061 & 0.330--3.413 &
0.921\tabularnewline
LVEDP \textgreater{} 15 mmHg & 1.155 & 0.419--3.186 & 0.781 & 1.302 &
0.396--4.285 & 0.664\tabularnewline
LVEF \textless{} 50\% & 3.666 & 1.319--10.114 & 0.012 & 4.712 &
1.478--15.016 & 0.009*\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: BNP=brain natriuretic peptide; LVEF=left ventricular
ejection fraction; HR=hazard ratio; CI=confidence interval; LVEDP=left
ventricular end-diastolic filling pressure

* p\textless{}0.05

\textbf{TABLE 5} Three-year clinical outcomes of patients with chronic
atrial fibrillation and a preserved ejection fraction\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Characteristics & LVEDP [?] 15 mmHg (n = 52) & LVEDP \textgreater{} 15
mmHg (n = 38) & \emph{p}\tabularnewline
\midrule
\endhead
All-cause mortality & 1 (1.9) & 0 (0.0) & 0.58\tabularnewline
Stroke & 0 (0.0) & 3 (7.9) & 0.07\tabularnewline
Hospitalisation & 8 (15.4) & 8 (21.1) & 0.58\tabularnewline
AF with RVR & 3 (5.8) & 0 (0.0) & 0.26\tabularnewline
Major bleeding & 1 (1.9) & 1 (2.6) & 0.67\tabularnewline
HF hospitalisation & 5 (9.6) & 3 (7.9) & 0.54\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: AF=Atrial fibrillation; RVR=rapid ventricular rhythm;
HF=heart failure; LVEDP=left ventricular end-diastolic filling pressure

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

\end{center}
\end{figure}

\textbf{Figure 1 Kaplan--Meier survival curves for patients with chronic
atrial fibrillation}

\textbf{a} Event-free rate of heart failure hospitalisation for patients
with REF (LVEF \textless{} 50\%) and those with PEF (LVEF [?]
50\%).\textbf{b} Event-free rate of heart failure hospitalisation for
patients with LVEDP [?] 15 mmHg and those with LVEDP \textgreater{} 15
mmHg. LVEDP=left ventricular end-diastolic filling pressure, LVEF=left
ventricular ejection fraction; PEF=preserved ejection fraction;
REF=reduced ejection fraction.

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

