Does atrial fibrillation affect plasma endothelin level?

Abstract

Atrial fibrillation (AF) may result in endocardial endothelium dysfunction. The main objective of the study was to evaluate the plasma concentration of endothelin-1 (ET-1) during persistent AF and after sinus rhythm recovery following direct-current cardioversion and to assess the predictive value of ET-1 in AF patients.
The study group consisted of 43 patients with persistent AF and normal left ventricle systolic function who had undergone successful cardioversion. Blood samples were collected twice: 24 hours before and 24 hours after cardioversion. All patients were also examined in terms of sinus rhythm maintenance on the 30th day after cardioversion.
There were no differences in ET-1 plasma concentration between the persistent AF group and the control group (2.6 ± 2.9 fmol/mL vs 2.3 ± 4.5 fmol/mL, NS). Plasma ET-1 levels did not change within 24 hours after successful cardioversion (2.5 ± 2.8 fmol/mL vs 2.6 ± 2.9 fmol/mL, NS). There was no correlation between the baseline plasma levels of ET-1 in patients with persistent AF and sinus rhythm maintenance 30 days after cardioversion.
Persistent AF does not affect plasma ET-1 concentration in patients with normal left ventricle systolic function and with no symptoms of heart failure. There are no significant changes in plasma ET-1 level during the 24 hours after cardioversion.

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www.cardiologyjournal.org
ORIGINAL ARTICLE
Cardiology Journal
2010, Vol. 17, No. X, pp. 1–x
Copyright © 2010 Via Medica
ISSN 1897–5593
Address for correspondence: Beata Wożakowska-Kapłon, PhD, 1st Clinical Department of Cardiology, Swietokrzyskie
Centre of Cardiology in Kielce, Grunwaldzka 45, 25–736 Kielce, Poland, tel./fax: +48 41 367 13 96,
e-mail: bw.kaplon@poczta.onet.pl
Received: 19.07.2009Accepted: 12.03.2010
Does atrial fibrillation affect
plasma endothelin level?
Beata Wożakowska-Kapłon1, 2, Radosław Bartkowiak1,
Grażyna Janiszewska3, Urszula Grabowska4
11st Clinical Department of Cardiology, Swietokrzyskie Centre of Cardiology, Kielce, Poland
2Faculty of Health Studies, University of Humanities and Science, Kielce, Poland
3Chair of Medical Biochemistry, Medical University of Lodz, Poland
4Central Laboratory, Swietokrzyskie Centre of Cardiology, Kielce, Poland
Abstract
Background: Atrial fibrillation (AF) may result in endocardial endothelium dysfunction.
The main objective of the study was to evaluate the plasma concentration of endothelin-1 (ET-1)
during persistent AF and after sinus rhythm recovery following direct-current cardioversion
and to assess the predictive value of ET-1 in AF patients.
Methods: The study group consisted of 43 patients with persistent AF and normal left
ventricle systolic function who had undergone successful cardioversion. Blood samples were
collected twice: 24 hours before and 24 hours after cardioversion. All patients were also
examined in terms of sinus rhythm maintenance on the 30th day after cardioversion.
Results: There were no differences in ET-1 plasma concentration between the persistent AF
group and the control group (2.6 ± 2.9 fmol/mL vs 2.3 ± 4.5 fmol/mL, NS). Plasma ET-1
levels did not change within 24 hours after successful cardioversion (2.5 ± 2.8 fmol/mL vs
2.6 ± 2.9 fmol/mL, NS). There was no correlation between the baseline plasma levels of ET-1
in patients with persistent AF and sinus rhythm maintenance 30 days after cardioversion.
Conclusions: Persistent AF does not affect plasma ET-1 concentration in patients with
normal left ventricle systolic function and with no symptoms of heart failure. There are no
significant changes in plasma ET-1 level during the 24 hours after cardioversion. (Cardiol J
2010; 17, x: xx–xx)
Key words: atrial fibrillation, endothelin, cardioversion
Introduction
The hemodynamic consequences of atrial fibril-
lation (AF) are related to the loss of atrial contribu-
tion to cardiac output, to an increase in heart rate
and to irregularity in the diastolic intervals. AF may
have a long term deleterious effect on left ventri-
cular function and may precede the development of
heart failure. It has been shown that patients with
AF and heart failure, but also with preserved left
ventricle (LV) function, have a similarly high mor-
tality compared to those patients with decreased left
ventricular ejection fraction (LVEF) [1]. AF and
chronic heart failure are two common cardiac

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Cardiology Journal 2010, Vol. 17, No. X
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diseases, affecting 1–2% of the population, a pro-
portion that rises with age [2, 3].
A pioneering work by Furchgott and Zawadzki [4],
published in 1980, initiated a new understanding of
vascular endothelium and its role as the main re-
gulator of vascular homeostasis. Endothelin type 1
(ET-1) is synthesized by the vascular endothelium
and is a sensitive biochemical marker of its dysfunc-
tion and damage. It exerts in a paracrine fashion
pleiotropic effects, including vasoconstriction, di-
rect chronotropism, growth effects on varying cell
types, and interactions with other neurohormonal
systems. ET-1’s influence on the overgrowth,
pathological reconstruction and fibrosis of atrial
muscle may be significant in AF pathophysiology.
The dysfunction and damage of vascular endotheli-
um are the cause of numerous pathologies and con-
stitute the main point of the theory of the continu-
um of the cardiovascular system’s disorders. The
disorders in the function of vascular endothelium
may occur in AF, which then may lead to increased
thrombogenesis and finally to the risk of stroke and
increased mortality. Elevated plasma concentra-
tions of ET-1, and of its precursor, have been mea-
sured in patients with various levels of severity and
etiology of chronic heart failure [5, 6]. These ob-
servations have led to the hypothesis that pharma-
cologic blockade of endothelin receptors could im-
prove outcomes for patients with chronic heart fail-
ure. However, clinical trials with different
endothelin receptor antagonists have not confirmed
these speculations [5, 6]. Studies published on the
subject do not include data on the possibilities of
the practical applications of ET-1 assessment in
patients with persistent AF, without symptoms of
overt heart failure, undergoing direct-current car-
dioversion (CV).
The main objective of this study was to evalu-
ate the plasma concentration of ET-1 in patients
with persistent AF with preserved LV function and
with no symptoms of heart failure, compared to a
control group before and after sinus rhythm recov-
ery, and to assess the prognostic importance of
these changes.
Methods
The examined group consisted of patients with
persistent AF, normal systolic function of LV and
no clinical symptoms of heart failure, who under-
went successful electrical CV. The main criteria for
inclusion were: persistent AF with no-valve etiol-
ogy, no contraindication for recovering sinus
rhythm by means of electrical CV, with preserved
LV function in echocardiography examination
(LVEF > 50%), no symptoms of heart failure, prop-
erly treated main disease (arterial hypertension,
coronary arterial disease, diabetes). The control
group consisted of ten people of a similar age, even-
ly divided as to men and women, treated in hospital
for circulatory system disorders (arterial hypertension
and coronary artery disease) with sinus rhythm and
preserved LV function, with no symptoms of heart fail-
ure and no history of AF.
All patients included in the study were exam-
ined three times: 24 hours before and 24 hours af-
ter CV and on the 30th day after sinus rhythm re-
covery. Clinical data, echocardiography readings
and laboratory determination before and after suc-
cessful CV were analyzed. In order to recover si-
nus rhythm, CV was performed with short general
anesthesia by means of a Medtronic Physio-Con-
trol Lifepak 12 with an electric discharge synchro-
nized with the electrocardiography R wave. The
procedure started with an initial 100 J. In cases of
persistent AF, we twice attempted to recover si-
nus rhythm with an impulse of 200 J. The maximum
energy delivered within one CV procedure did not
exceed 500 J. The CV efficiency was defined as the
lack of AF in the 24th hour after the recovery of si-
nus rhythm.
The transthoracic echocardiography was per-
formed with the use of a digital Siemens device,
Acuson Sequoia C 256, with an ultrasonic head with
frequency of 2.5–3.5 MHz.
Blood samples for ET-1 concentration were
collected into EDTA test tubes in the morning
hours by means of venipuncture from fasting pa-
tients. The blood was centrifuged at a temperature
of 4°C and plasma was frozen at a temperature of
–20°C. The ET-1 plasma concentration was marked
by means of an ELISA test using an Endothelin ELISA
(1-21) Biomedica set no. BI-20052. After successful
CV, most patients underwent anti-arrhythmic treat-
ment. The statistical analyses were conducted by
means of SYSTAT 7.0 and MedCalc 4.16 software.
Permission for conducting the examination was ob-
tained from the National Committee on Bioethics.
Results
Initially, 45 patients aged 18–75 were qualified
for the study. Finally, 43 subjects with successful
CV were included. Patients’ characteristics are list-
ed in Table 1. The main risk factors of AF occur-
rence in the study group were arterial hypertension,
ischemic heart disease and diabetes. The patients
from the control group were compatible in age and

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Beata Wożakowska-Kapłon et al., Endothelin-1 in atrial fibrillation
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gender and did not differ in baseline clinical and
echocardiographic data. During the first visit (24 h
before CV), the average heart rhythm frequency
was 85.4 ± 13.2 bpm, systolic and diastolic blood
pressure were normal. The LVEF was of about 57%
in the study group. The left atrium diastolic diame-
ter was 43.7 ± 5.9 mm and did not differ significant-
ly when compared to the control group. ET-1 plas-
ma concentration in patients with persistent AF was
2.6 ± 2.9 fmol/mL and did not differ significantly in
comparison to the control group (2.3 ± 4.5 fmol/mL).
In patients with persistent AF who underwent suc-
cessful CV, plasma ET-1 concentration evaluated
24 hours after the recovery of sinus rhythm (2.5 ±
± 2.8 fmol/mL) did not differ significantly from the
samples measured 24 hours before CV (2.6 ±
± 2.9 fmol/mL). Plasma ET-1 concentrations in the
group of patients 24 hours before and 24 hours
after CV are presented in Figure 1. Within the
24 hours following CV, all 43 patients maintained
sinus rhythm. But after 30 days, sinus rhythm with-
out registered episodes of AF was maintained in
24 (56%) patients. Depending on the presence of
sinus rhythm on the 30th day after CV, the entire
group was divided into two sub-groups: subgroup A,
patients with sinus rhythm in a 30-day follow-up
from CV; and subgroup B, patients with AF relapse
in a 30-day observation period.
Neither subgroup differed in terms of the basic
clinical and echocardiographical parameters evalu-
ated by CV. There were no statistically significant
differences in the frequency of occurrence of the
concomitant circulatory system disorders (coronary
heart disease, arterial hypertension or stroke) as
well as diabetes in both subgroups. Additionally,
neither group differed in terms of the anti-arrhyth-
mic treatment after CV. There were also no differ-
ences in the frequency of the administration of an-
giotensin-converting enzyme inhibitors (Table 2).
The ET-1 plasma concentration, determined before
CV, did not differ significantly between the patients
without AF relapse (subgroup A) and the patients
with AF recurrence (subgroup B) and was 3.1 ± 3.8
fmol/mL vs 2.0 ± 1.4 fmol/mL respectively,
p = 0.25). In order to assess the prognostic value
of the ET-1 measurement in patients with persis-
tent AF referred to direct-current CV, the logistic
regression method was applied. There turned out
to be no correlation between the initial ET-1 plas-
ma concentration and the maintenance of sinus
rhythm 30 days after CV (p = 0.24).
Table 1. The study group’s baseline characteristics.
ParameterStudy group (n = 43)Control group (n = 10)p
Age (years)
Gender: women/men
Body mass index [kg/m2]
Heart rate [beats/min]
Systolic blood pressure [mm Hg]
Diastolic blood pressure [mm Hg]
Hypertension
Coronary artery disease
Diabetes
Lone atrial fibrillation
Atrial fibrillation duration (weeks)
Left ventricular ejection fraction (%)
Left atrium dimension [mm]
59.0 ± 11.6
8 (18.6%)/35 (81.4%)
28.5 ± 3.8
85.4 ± 13.0
130.6 ± 14.9
80.3 ± 9.0
27 (62.8%)
8 (18.6%)
3 (7.0%)
9 (20.9%)
12.3 ± 15.3
57.3 ± 6.1
43.7 ± 5.9
57.5 ± 9.2
2 (20%)/8 (80%)
26.7 ± 4.3
80.4 ± 16.5
131.0 ± 17.3
81.0 ± 8.7
7 (70%)
3 (30%)
2 (20%)
—
—
61.6 ± 6.8
41.0 ± 4.4
NS
NS
NS
NS
NS
NS
NS
NS
NS
—
—
NS
NS
Figure 1. Plasma endothelin-1 levels before and after
successful cardioversion (CV) in 43 patients with persi-
stent atrial fibrillation.

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Discussion
This study presents the outcome of the evalu-
ation of ET-1 plasma concentration in patients with
persistent AF before CV and after sinus rhythm
recovery. The usefulness of the endothelium func-
tion evaluation for prognosis of the disease’s course,
as well as the possible response to treatment, was
analyzed. The study included both patients with
spontaneous AF and those with AF triggered by hy-
pertension or coronary heart disease, with no symp-
toms of heart failure, normal LV systolic function,
short duration time of arrhythmia (approximately
three months) and successful CV with sinus rhythm
recovered.
There are few studies on peptides of the en-
dothelin family concerning AF patients. Tuinenburg
et al. [7] in 1998 pointed to ET-1 as an important
factor responsible for the fibrosis of atrial myocytes
in persistent AF. Masson et al. [8] described high-
er ET-1 plasma concentrations in patients with
chronic heart failure and accompanying AF in com-
parison to the patients with no arrhythmia [8].
So far, no research has been carried out on the
influence of AF on ET-1 plasma concentration in
patients with normal LV systolic function and no
symptoms of heart failure. The mechanisms respon-
sible for the increased release of ET-1 in patients
with AF are not well recognized. Atrial volume and
pressure overload due to the lack of synchronized
contraction of atria and irregular ventricular rhythm
may lead to endothelium dysfunction in AF [9, 10].
The mechanism which increases ET-1 plasma con-
centration may be the increased peptide secretion
and release of endothelium from the damaged cells
within the cardiac cavities [11]. Brundel et al. [12]
state that within the damaged endothelium in pa-
tients with AF, there is an increased gene expres-
sion for ET-1, increased synthesis and release of
active peptide. The increased ET-1 plasma concen-
tration in patients with AF may stimulate the pro-
liferation of smooth muscle cells and fibroblasts,
which could lead to overgrowth and fibrosis. ET-1
may also trigger the inflammation process through
the stimulation of cytokine production, growth and
transformation factors as well as the intensification
of leukocyte migration [13, 14]. ET-1 may also influ-
ence the electrical remodeling of atrial cardiomyo-
cytes through increased intracellular calcium ions
concentration [15, 16]. The influence of ET-1 on the
renin–angiotensin–aldosterone system takes place
through the stimulation of aldosterone release, which
plays an important role in the structural, electrical
and neurohormonal remodeling of atriums [17, 18].
In our study, we noticed that ET-1 concentra-
tion was not higher in the study group than in the
control group, (2.6 ± 2.9 fmol/mL vs 2.3 ± 4.5 fmol/
mL, NS respectively). The frequent occurrence of
arterial hypertension and type 2 diabetes mellitus
in both groups, associated with the dysfunction of
the endothelium and increased ET-1 plasma con-
centration, may have had some impact on the re-
sults obtained [19, 20]. However, early-stage atrial
disease in the examined group of patients may also
have some influence on the results. Our findings are
in contrast to the Dézsi et al. [21] study. These
authors described a rapid decrease of ET levels af-
ter catheter ablation, suggesting that a high ven-
tricular rate could be a trigger of ET production.
Patients in our study had well-controlled ventricu-
lar rates (average 85 bpm, whereas in the Dézsi
study the rates were about 110–170 bpm). A detailed
evaluation of the importance of the pathophysiolo-
gical role of the endothelin system in AF requires
further research on a larger group of patients.
In the group examined, there were no impor-
tant changes in ET-1 plasma concentrations in the
first 24 hours after CV. It may be assumed that the
recovery of sinus rhythm by treating the hemody-
namic disorders which are associated with AF leads
Table 2. The study subgroups’ baseline characteristics.
ParameterSubgroup A
(sinus rhythm)
n = 24
Subgroup B
(atrial fibrillation)
n = 19
p
Age (years)
Heart rate [beats/min]
Systolic blood pressure [mm Hg]
Atrial fibrillation duration (weeks)
Left ventricular ejection fraction (%)
Left atrium dimension [mm]
60.1 ± 10.3
85.5 ± 13.7
133.2 ± 14.5
12.6 ± 18.1
57.8 ± 5.9
43.4 ± 5.9
57.7 ± 13.6
85.3 ± 12.9
127.4 ± 15.7
12.0 ± 11.0
56.5 ± 6.5
44.0 ± 6.1
NS
NS
NS
NS
NS
NS

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Beata Wożakowska-Kapłon et al., Endothelin-1 in atrial fibrillation
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to an improvement in the function of the endotheli-
um. Although successful CV results in heart rhythm
stabilization and in a decrease of rhythm frequen-
cy, it most probably does not lead to a significant
improvement in the endothelium function within
24 hours after the procedure [22]. We observed that
the increased ET-1 plasma concentration was main-
tained from two to seven days after a myocardial
infarction or in acute coronary syndrome, which are
undoubtedly associated with acute endothelium
dysfunction of the coronary vessels [23, 24]. It may
also be assumed that the function of the endotheli-
um is not heavily disturbed in patients with arrhyth-
mia (lasting for a short period of time, on average
for 12 weeks) and in patients with normal LV sys-
tolic function and no symptoms of heart failure. An-
other reason for such results may be relatively wide
ranges of ET levels in both AF and control groups,
and inclusion of patients with co-morbidities e.g.
diabetes, coronary heart disease, hypertension,
obesity.
Predictors most frequently referred to as use-
ful in the prognosis of CV outcome for patients with
AF are: patients’ age, duration of arrhythmia, arte-
rial hypertension or valvular heart disease [25–27].
The only echocardiographical parameter with
a clearly defined negative prognostic value is the
significant enlargement of the left atrium, exceed-
ing 60 mm [28, 29]. In patients with congestive
heart failure, ET-1 concentration was a better pre-
dictor of general mortality than natriuretic peptides
[30]. The increased production and release of ET-1
through the damaged endothelium my lead to the
intensification of fibrosis processes and unfavorable
outcomes of AF direct-current CV. Therefore, it
may be assumed that AF recurrence after the re-
covery of sinus rhythm would be more frequent in
patients with high initial ET-1 plasma concentra-
tions. However, in the examined group of patients
with persistent AF with normal LV systolic func-
tion, there was no association between the basal
ET-1 plasma concentration and the maintenance of
sinus rhythm in a period of 30 days after CV. This
is the first study assessing ET-1 in AF with normal
LV systolic function and has come up with contro-
versial results. The issue needs further study.
Limitations of the study
Our cohort represents a non-homogenous
group of patients, clinically stable but with histo-
ries of hypertension, coronary artery disease or
diabetes, and with diverse duration times of AF
(seven days to 19 months). No other markers of
possible systemic inflammation (CRP-hs, interleu-
kins) with probable relation to ET levels were ex-
amined. Furthermore, the present study has the
inherent limitation of its relatively small number of
patients. However, to our knowledge, the present
study is the first to assess ET-1 in AF with normal
LV systolic function after CV (not only baseline con-
centration) as predicting rhythm stability after CV.
Therefore the present study offers valuable new
insights. We examined patients referred by their
primary care physician to CV. The study does not
take into account the patients (asymptomatic, un-
detected or without consent to CV) who were not
referred. It would be important to replicate our find-
ings in a larger cohort in order to confirm the data
presented.
Conclusions
1.Persistent AF in patients with normal LV sy-
stolic function and with no symptoms of heart
failure does not lead to an increase in ET-1 pla-
sma concentrations compared to patients with
sinus rhythm.
The recovery of sinus rhythm following elec-
trical CV in patients with persistent AF does
not lead to a significant increase in ET-1 pla-
sma concentration.
Plasma ET-1 concentration is not a predictor
of the maintenance of sinus rhythm in a period
of 30 days after successful CV.
2.
3.
Acknowledgements
The authors do not report any conflict of inte-
rest regarding this work.
This study was supported by the Polish Com-
mittee for Scientific Research, grant KBN 2 P05B
034 26.
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