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Biochemical predictors of cardiac rhythm at 1 year follow-upin patients with non-valvular atrial fibrillation
Monica Acevedo • Ramon Corbalan •
Sandra Braun • Jaime Pereira • Ilse Gonzalez •
Carlos Navarrete
Published online: 3 February 2012
� Springer Science+Business Media, LLC 2012
Abstract C-reactive protein (CRP) is increased in
patients with atrial fibrillation (AF) and it might predict the
lack of sinus rhythm maintenance in the long term follow-
up. Scarce data have been reported relating endothelial
dysfunction and/or haemostatic or platelet markers to sinus
rhythm maintenance in AF patients. We aimed to deter-
mine whether some biochemical markers including soluble
thrombomodulin (sTM), soluble P-selectin, thrombin–
antithrombin (TAT) complex and CRP levels could predict
sinus rhythm maintenance at 1 year follow-up in non-val-
vular AF patients. 130 patients (70 males, mean age 67 ±
13 years) with newly diagnosed AF naıve of antithrom-
botic or antiplatelet therapy were studied. Baseline CRP,
P-selectin, sTM and TAT levels were compared to those of
20 matched-healthy subjects in sinus rhythm. AF patients
had significantly higher plasma CRP (10.5 ± 2.2 vs 3.25 ±
0.3 mg/l, p = 0.001), P-selectin (219 ± 141 vs 126 ng/ml,
p = 0.01), and TAT (54 ± 237 vs 2.7 ± 3.3 ng/l, p =
0.001) levels compared with controls. Soluble TM levels,
although higher than controls, did not reach statistical
significance. Multivariate regression analyses showed that
elevated CRP (OR = 4.8, p = 0.02) and sTM (OR = 1.05,
p = 0.04) were the only two predictors of lack of sinus
rhythm at 1 year follow-up. An altered inflammatory,
haemostatic, endothelial and platelet environment exists in
newly diagnosed AF patients. CRP and sTM levels might
be used as biochemical markers to predict the status of
cardiac rhythm at 1 year follow-up in some AF patients.
Keywords Atrial fibrillation � C-reactive protein �Soluble thrombomodulin � Cardiac biomarkers �Cardiac rhythm
Introduction
Atrial fibrillation (AF) is the most prevalent arrhythmia in
clinical practice and it is associated with an increased risk
of morbidity and mortality [1]. Several studies have dem-
onstrated the existence of a prothrombotic state in patients
with AF [2–6] which might be associated with a higher
incidence of embolic events. On the other hand, recent
studies have shown that at the same time, patients with AF
have an alteration in endothelial and platelet function [3, 7,
8]. The latter could contribute to hypercoagulability, and
therefore, to an increased risk of thromboembolic events in
these patients [9].
Our group [10] and other investigators [11, 12] have
demonstrated the existence of a systemic inflammatory
state characterized by the elevation of C-reactive protein
(CRP) plasma levels in patients with non-valvular AF.
Other groups have also published about an elevation in
other inflammatory markers in AF patients, such as ICAM,
VCAM [13] and IL-6 among others [14, 15]. Nevertheless,
the clinical significance of this inflammatory state in AF
patients remains to be elucidated. It appears important to
establish if there is an association among these altered
biochemical markers and the long term cardiac rhythm in
M. Acevedo (&) � R. Corbalan � S. Braun � I. Gonzalez
Facultad de Medicina, Division de Enfermedades
Cardiovasculares, Pontificia Universidad Catolica de Chile,
Lira 85, 1st Floor, Santiago, Chile
e-mail: macevedo@med.puc.cl
J. Pereira
Facultad de Medicina, Departamento de Hematologıa,
Pontificia Universidad Catolica de Chile, Santiago, Chile
C. Navarrete
Departamento de Matematicas, Universidad de la Serena,
La Serena, Chile
123
J Thromb Thrombolysis (2012) 33:383–388
DOI 10.1007/s11239-012-0690-1
these patients. We reported that elevated CRP levels in AF
patients predicted a lower chance of sinus rhythm main-
tenance in these patients at 1 year follow-up [10]. In the
present study, we have hypothesized that elevated CRP
levels (a well-known systemic inflammatory marker), sTM
levels (a marker of endothelial dysfunction) and P-selectin
(marker of platelet activation), are independent biochemi-
cal predictors of sinus rhythm maintenance in the long term
in patients with non-valvular AF. In addition, we have
evaluated whether a prothrombotic state, determined by
determinations of thrombin–antithrombin (TAT) levels,
correlate with the other biochemical markers included in
this study.
Methods
We prospectively and consecutively recruited all the
patients admitted to the Catholic University Hospital with
newly diagnosed AF between March 2005 and November
2007 (n = 130) who were not receiving anticoagulation or
antiplatelet therapy. All the patients were evaluated by the
cardiologists in charge of the study at baseline (admission),
at 30 days and at 1 year follow-up.
We included patients with newly diagnosed AF, whether
they had paroxysmal or persistent non-valvular AF. We used
the European Society of Cardiology guidelines. The control
group consisted of 20 subjects, matched by age and gender in
sinus rhythm, without reported history of previous arrhythmia,
cardiomyopathy and/or use of anticoagulant or antiplatelet
drugs. We excluded all the patients who were on anticoagu-
lants or antiplatelet medications, those having an acute coro-
nary syndrome\60 days before admission, patients with AF
secondary to acute pericarditis or myocarditis, those with AF
secondary to pulmonary thromboembolism, cardiac surgery,
alcoholic abuse, and/or hyperthyroidism, and those with
infectious, inflammatory, renal or hepatic diseases. Upon
admission, we systematically reviewed all the clinical and
echocardiographic risk factors for systemic embolism. We
recorded age, history of hypertension, diabetes, previous heart
disease and systemic embolism. A transthoracic and trans-
esophageal echocardiogram (TEE) was performed in all the
patients within the first 24 h of admission to the hospital
(Hewlett Packard, Sonos 5500). We measured left atrial (LA)
diameter, left systolic and diastolic ventricular (LV) diameters,
left ventricular ejection fraction (LVEF), diastolic LV function
and left atrial appendix (LAA) function. We also recorded the
existence of spontaneous LA echo contrast and/or thrombus.
We ruled out the presence of atherosclerotic plaques in main
aorta, the presence of a patent foramen oval and valvular
abnormalities.
At admission, and before the administration of antiar-
rhythmic and/or anticoagulant medications, venous plasma
samples for CRP, TAT, P-selectin, sTM and general lab-
oratory (creatinine, hepatic enzymes, thyroid hormones,
red and white blood count and erythrosedimentation rate)
determinations were taken.
Laboratory determinations
Blood samples were drawn by the study coordinator of the
study in all the patients and controls. Measurements of
CRP were assayed by turbidimetric method (sensitivity
\ 0.03 mg/dl) [16]. Concentrations of TAT plasma levels
were performed using an ELISA sandwich method
(Enzygnost TAT micro, Behring). Soluble TM levels were
measured by ELISA technique (R&D Systems, Abingdon,
United Kingdom). Intra-assay coefficients of variation for
all ELISA assays were \5%. P-selectin levels were deter-
mined by flow cytometry. Multiparameter flow cytometry
immunophenotypic studies were performed in EDTA-
anticoagulated peripheral blood samples. In all cases the
analysis was performed on erythrocyte-lysed samples using
well-established stain, lysis and wash procedures. For that
purpose a panel of monoclonal antibodies (MoAb) in
2-color stainings—fluorescein isothiocyanate (FITC) and
phycoerythrin (PE)—were used. In all samples a combined
staining for surface antigens directed against CD41 (in
order to recognize platelets) and CD62P was performed.
For data acquisition, a FACSCalibur flow cytometer and
the CellQUEST software (Becton–Dickinson Biosciences
(BDB), San Jose, CA, USA) were used, acquiring a total of
10,000 events per sample. The Paint-A-Gate PRO software
program (BDB) was employed for data analysis.
Follow-up
Patients were followed at 30 days and 1 year to obtain
clinical relevant information about cardiac rhythm, sys-
temic embolism and adherence to treatment, and for new
determinations of CRP, TAT, sTM and P-selectin plasma
levels. During follow-up, maintenance or recurrence of AF
or maintenance of sinus rhythm were determined by a
resting EKG. Chronic pharmacological treatment for AF
depended on the attending physicians.
The study was approved by the Ethics Committee of the
Faculty of Medicine of the Pontificia Universidad Catolica
de Chile. All the patients had to sign an informed consent
before entering the study.
Statistics
Results are presented as mean plus/minus standard devia-
tion. AF group was compared to control group using ‘‘t’’
test for independent variables when parameters were nor-
mally distributed, and non-parametric test (Wilcoxon rank
384 M. Acevedo et al.
123
sum) otherwise. Fisher exact test was used for categorical
variables. We considered significant a p \ 0.05. Logistic
regression analyses was used for predictors of cardiac
rhythm at 1 year follow-up.
Results
Of the 130 studied patients (70 men), 80 resulted to have
paroxysmal AF and 50 evolved to persistent AF. Clinical and
echocardiographic characteristics of the group are shown in
Table 1. Mean age of the group was 67 ± 13 years. Patients
with paroxysmal AF were statistically significantly younger
than those with persistent AF, and had less echocardiographic
risk factors for systemic embolism. No differences were
noted between the two groups in relation to history of
hypertension, diabetes, heart disease and systemic embolism
(Table 1). At 1 year follow-up, there was no difference
between the number of patients taking amiodarone or bblockers in the two groups. We did not have any clinical
episodes of ischemic stroke and/or systemic embolism during
the 1 year follow- up.
Plasma CRP levels at entry were 10.5 ± 2.2 mg/l in AF
individuals and 3.25 ± 0.4 mg/l in controls (p = 0.001 versus
controls). There were no significant differences in CRP levels
between paroxysmal and persistent AF groups (9.25 ± 2.1 vs.
11.3 ± 2.4 mg/l, paroxysmal versus persistent AF respec-
tively, p = 0.6). Baseline TAT levels confirmed a prothrom-
botic state in AF patients (54 ± 237 vs 2.7 ± 3.3 ng/ml in
controls, p \0.001). Baseline TAT levels were significantly
higher in patients with persistent AF compared to those with
paroxysmal AF (95 ± 376 vs 28 ± 61 ng/ml, p = 0.02).
Baseline P-selectin levels were also significantly higher in AF
patients than controls (219 ± 141 ng/ml vs 145 ± 29 ng/ml,
p = 0.01). No differences were found in P-selectin levels
between paroxysmal and persistent AF. Finally, although sTM
levels at entry were higher in AF group than controls, the
difference was not significant (52.2 ± 111 vs 44 ± 13 ng/ml,
respectively; Table 2), neither was the difference between
paroxysmal and chronic AF (43 ± 35 vs 66 ± 171, parox-
ysmal versus persistent AF respectively). We did not find any
correlations among CRP, P-selectin, TAT and sTM levels and
the clinical and echocardiographic studied parameters. A sig-
nificant correlation was found between TAT and P-selectin
(r = 0.3, p = 0.02).
At 30 days and 1 year follow-up: CRP levels were
5.6 ± 8.9 and 4.9 ± 6.6 mg/l, respectively; sTM levels =
40.3 ± 24.3 and 42.9 ± 34 ng/ml, respectively; P-selectin =
167.6 ± 136 and 138 ± 124 ng/ml and TAT levels 6.9 ± 18
and 9.5 ± 43 ng/ml, respectively. Thus, CRP levels decreased
significantly at 30 days (p \0.001) and 1 year follow-up
(p\ 0.001) in comparison to baseline levels. P-selectin and
sTM levels also decreased at 30 days and 1 year, but in both the
drop was not significant compared to baseline levels. Finally,
TAT levels also decreased, as expected with anticoagulation, at
both 30 days and 1 year (p = 0.04 and p = 0.02, respectively
compared to baseline levels).
Using multivariate analyses we modeled the probability
(Odds Ratio) of lack of sinus rhythm at 1 year follow-up.
In this model (Table 3) we included age, LA diameter, left
ventricular diastolic diameter, LV systolic function, and
LAA contractile function, along with baseline CRP, TAT,
P-selectin and sTM levels (Table 3). According to this
model, baseline CRP (OR = 4.8, CI = 1.2–22) and sTM
(OR = 1.05, CI = 1.006–1.12) levels were significant and
independent predictors of the lack of maintenance of sinus
rhythm at 1 year follow-up in AF patients, whether they
belonged to the paroxysmal or the persistent AF group
(Table 4).
The differences (delta) between baseline levels and
30 days and baseline levels and 1 year follow-up levels of
the different determinations (CRP, sTM, P-selectin and
Table 1 Clinical and echocardiographic characteristics of the
patients
Variable AF group
n = 130
Paroxysmal
AF
n = 80
Persistent
AF
n = 50
Age (years) 67 ± 14 65 ± 16 70 ± 9
Heart rate 118 ± 30 128 ± 28 102 ± 2
Hypertension (%) 59 54 63
Diabetes (%) 15 19 13aCardiomyopathy (%) 34 32 43
Previous embolism (%) 6 7 3
LA [45 mm (%) 54 41 90
Spontaneous echo contrast
and/or thrombus (%)
52 47 69
LV dysfunction (%) 15 10 23
a Hypertensive or dilated cardiomyopathy; LA left atrium, LV left
ventricle
Continuous variables are presented as mean ± standard deviation and
categorical variables as percentages
Table 2 Baseline plasma levels of C-reactive protein, soluble
thrombomodulin, thrombin–antithrombin complex and P-selectin in
patients with newly diagnosed non-valvular atrial fibrillation
Biochemical biomarker Control AF group p
C-reactive protein (mg/l) 3.3 ± 2.3 10.5 ± 2.2 0.001
Soluble thrombomodulin (ng/ml) 44 ± 13 52.2 ± 111 0.09
Thrombin–antithrombin complex
(ng/l)
2.7 ± 3.3 54 ± 237 0.001
P-Selectin (ng/ml) 145 ± 29 219 ± 141 0.01
Biochemical predictors of cardiac rhythm 385
123
TAT) were not predictors of lack of sinus rhythm main-
tenance at 1 year.
Discussion
This study confirms the existence of elevated CRP, sTM,
P-selectin and TAT levels in patients with newly diagnosed
non-valvular AF. At the same time, it demonstrates that
CRP and sTM levels are predictors of the persistence of the
arrhythmia at 1 year follow-up.
The occurrence of AF is common in acute and chronic
inflammatory disorders [17]. Thus, AF is found in 25–40%
of patients after coronary by-pass surgery [18]. In this
clinical condition an acute elevation of proinflammatory
cytokines, such as interleukin-6 and later, CRP exists. AF
also occurs in other acute inflammatory conditions, like
infectious diseases, thyrotoxicosis and alcohol intoxication
[17]. The underlying anatomic evidence of the inflamma-
tory process has been shown in atrial biopsies of patients
with refractory AF [19].
Inflammation plays a crucial role in atherosclerotic
cardiovascular disease [20, 21]. Today, it is well accepted
that CRP is an important risk marker for cardiovascular
diseases, particularly for hard endpoints, such as myocar-
dial infarction and ischemic stroke in populations without
known cardiovascular disease [22–24]. CRP levels also
predict subsequent coronary events in both stable and
unstable angina [25]. It has been demonstrated that CRP
induces complement activation [26], the expression of
adhesion molecules [27] and the production of tissue factor
in the endothelium. Finally, CRP attenuates nitric oxide
production and it inhibits angiogenesis [28]. In summary,
CRP contributes to the presence of endothelial dysfunction
and thrombogenesis.
Our first observations of CRP elevation in non-valvular AF
patients [10] confirmed and expanded the results of Chung
et al. [11]. These authors demonstrated, in a retrospective
case–control study, that CRP levels were elevated in 131
patients with supraventricular tachyarrhythmias (paroxysmal
and persistent AF and other supraventricular arrhythmias).
However, their results as well as ours, did not clarify whether
this elevation was the cause or the consequence of the
arrhythmia. In our study it is noteworthy that CRP levels at
baseline were predictors of cardiac rhythm at 1 year, inde-
pendently of other clinical and/or echocardiographic variables.
In the present study, we have confirmed our previous
findings about the probable prognostic significance of high
baseline CRP levels in AF patients [10]. In that report, we
communicated that high CRP levels in newly diagnosed
AF could predict the maintenance of the arrhythmia in the
long term. In this regard, some authors have reported that
inflammation contributes in the remodeling process of the
atrium in AF patients [29]. Nevertheless, it remains to be
determined whether CRP elevation only is a consequence
of the remodeling phenomena in the left atrium or it con-
tributes to the occurrence of the arrhythmia.
The present study provides some new information on the
mechanisms involved in AF. We here report endothelial
dysfunction mediated by sTM, a known marker of endo-
thelial damage. Soluble TM elevation has been reported in
patients with hypertension, peripheral vascular disease and
coronary heart disease, and it is associated with a higher
incidence of thromboembolic events [7, 30–33]. Soluble
TM is a constitutive membrane protein. It regulates
thrombin activity on the endothelial surface. Soluble TM
also activates the anticoagulant protein C on the endothe-
lium through an interaction of sTM with the endothelial
cell [30]. For this reason, elevated sTM levels in plasma
have been attributed to the liberation of the protein from
endothelial cells secondary to endothelial damage. If this
were the case, elevated sTM plasma levels could be asso-
ciated with a higher of thromboembolic events because of
the conditioning for a procoagulant state on the endothelial
surface. In this report, elevated sTM levels were signifi-
cantly associated to the persistence of the arrhythmia in the
long-term follow-up. Our findings show an association
between the maintenance or recurrence of AF in the long-
term with inflammatory or endothelial parameters, i.e. CRP
and sTM respectively.
Table 3 Predictors of sinus rhythm maintenance at 1 year follow-up
(multivariate analyses)
Parameter p
C-reactive protein 0.02
Soluble thrombomodulin 0.04
Age 0.18
Left ventricular dysfunction 0.94
Left atrium \45 mm 0.45
Left ventricle (diastole) \56 mm 0.14
Left atrial appendage shortening 0.54
Table 4 Adjusted relative risk of lack of sinus rhythm at 1 year
follow-up
Parameter interval Odds
ratio
95% Confidence
interval
C-reactive protein 4.8 1.3–22
Soluble thrombomodulin 1.053 1.01–1.12
Age 1.038 0.98–1.1
Left ventricular dysfunction 0.931 0.1–9.9
Left atrium \45 mm diameter 0.576 0.1–2.5
Left ventricle diastole\56 mm 0.169 0.01–1.7
Left atrium appendage
shortening
0.992 0.9–1.02
386 M. Acevedo et al.
123
A report of Yamashita et al. [34] give support to our
results. These authors demonstrated that rapid atrial pacing
in rats produced an alteration in gene expression of TM and
tissue factor inhibitor in atrial endocardium. These findings
suggested that the tachycardia induced by atrial pacing
produced an alteration in the synthesis of TM. In patients,
elevated circulatory sTM levels have been reported [3, 13].
The elevation of circulating sTM levels in this study was
explained as to a higher release of TM from the damaged
atrial endocardium of patients with AF. Our results are in
agreement with these findings.
We also found higher P-selectin levels in our patients.
This finding has been previously reported by others
(6,34,35). Elevation of P-selectin levels, along with TAT
plasma levels in patients with AF, supports the existence of
a prothrombotic state in these patients. The coexistence of
an activation of coagulation, endothelial damage and
platelet activation in patients with AF might translate into a
higher incidence of embolic events [35].
Finally, it was interesting to note that none of the
echocardiographic variables demonstrated to be predictors
of cardiac rhythm at 1 year follow-up when compared with
sTM or CRP. Only when the biochemical markers were
taken off from the model, LA size, LV function and LAA
function became predictors of sinus rhythm maintenance
during the long-term follow-up.
The results of the present study could contribute to the
investigation for new therapeutic alternatives in AF
patients. It has been published that AF patients treated with
glucocorticoids for 4 months, in addition to antiarrhythmic
therapy, lowered CRP levels. These results also associated
with less recurrence rate of AF(36). Statins also have an
anti-inflammatory effect. A recent communication in this
respect found that subjects taking statins had a lower
prevalence of AF [36].
Our study has several limitations: (1) This study was
done in a university hospital, therefore, a selection bias
exist in the study population. Control subjects were mat-
ched only for age and gender. We can not tell about other
risk factors in these subjects that could have influenced the
results. (2) The results were adjusted only for the most
common variables that could have changed results, i.e.
demographic variables, echocardiographic variables and
antiarrhythmic drugs. We did not adjust for other drugs,
such as statins or estrogens that could have influenced the
results. (3) Small sample that precluded possible interac-
tions. (4) Need for a longer follow-up to establish risk of
systemic embolism or other cardiovascular events.
In conclusion, the present study confirms the existence
of elevated CRP, sTM and P-selectin levels in patients with
newly diagnosed non-valvular AF, and it demonstrates that
high baseline CRP and sTM levels are independent pre-
dictors of cardiac rhythm at 1 year follow-up.
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