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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