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Systemic inflammation and left atrial thrombus in patients with non-rheumatic atrial fibrillation.

Journal of Cardiology(2010)56,118—124

Systemic inflammation and left atrial thrombus in patients with non-rheumatic atrial fibrillation.

Systemic inflammation and left atrial thrombus in patients with non-rheumatic atrial fibrillation.

Systemic inflammation and left atrial thrombus in patients with non-rheumatic atrial fibrillation.

Original article

Systemic in?ammation and left atrial thrombus in patients with non-rheumatic atrial?brillation

T omoko Maehama(MD)?,Hiroyuki Okura(MD,PhD,FJCC),

Koichiro Imai(MD),Ken Saito(MD),Ryotaro Yamada(MD,PhD),

Terumasa Koyama(MD),Akihiro Hayashida(MD),Yoji Neishi(MD,PhD), Takahiro Kawamoto(MD,PhD),Kiyoshi Yoshida(MD,PhD,FJCC)

Department of Cardiology,Kawasaki Medical School,Matsushima577,Kurashiki,Okayama701-0192,Japan

Received2February2010;received in revised form4March2010;accepted19March2010

Available online13May2010

KEYWORDS

In?ammation;

Atrial?brillation;

Echocardiography;

Thrombus

Summary

Background:There is an apparent link between thrombogenesis and in?ammation.We

hypothesized that systemic in?ammation[as indicated by C-reactive protein(CRP)]would be

related to the presence of left atrial(LA)thrombus in patients with atrial?brillation(AF).T o

test this hypothesis,we evaluated the relationship between CRP and LA thrombus in patients

with non-rheumatic AF.

Methods and results:Between October2004and December2008,190patients with non-

rheumatic AF(122males,age71±10years)who underwent transesophageal echocardiography

(TEE)were enrolled and analyzed.All patients were examined for presence or absence of LA

thrombus by TEE.CRP was measured within1week before the TEE http://www.wendangku.net/doc/c953868683d049649b665840.html thrombus

was detected in19patients(10%).Hypertension,hypertensive heart disease(HHD),valvular

heart disease,ticlopidine,and CRP were univariate correlates of LA thrombus.By multivariate

analysis,HHD(p<0.01),ticlopidine(p=0.01),and CRP(p=0.03)were independently associated

with LA thrombus.A cut-off CRP value for identifying LA thrombus was0.21mg/dl(sensitivity:

84%,speci?city:60%,positive predictive value:19%,and negative predictive value:97%).

Conclusion:A high CRP is related to LA thrombus in patients with non-rheumatic AF.

?2010Japanese College of Cardiology.Published by Elsevier Ireland Ltd.All rights reserved.

?Corresponding author.T el.:+81864621111;

fax:+81864644060.

E-mail address:tmaehama@med.kawasaki-m.ac.jp

(T.Maehama).

Introduction

Atrial?brillation(AF)is a common arrhythmia that repre-

sents an independent risk factor for systemic as well as cere-

bral embolism[1].Abnormalities of hemostasis,?brinolysis,

endothelium,and platelet function in AF may increase the

risk of stroke and thromboembolism[2,3].These prothrom-

botic states in addition to left atrial(LA)blood stasis may be

0914-5087/$—see front matter?2010Japanese College of Cardiology.Published by Elsevier Ireland Ltd.All rights reserved.

doi:10.1016/j.jjcc.2010.03.006

In?ammation and left atrial thrombus119

associated with LA thrombus and spontaneous echo contrast (SEC)[3].Transesophageal echocardiography(TEE)has been widely and reliably used to detect LA thrombus and SEC with high accuracy[4—6].On the other hand,there is an apparent link between thrombogenesis and in?ammation[7—10].We hypothesized that systemic in?ammation[as indicated by C-reactive protein(CRP)]would be related to the presence of LA thrombus in patients with AF.T o test this hypothesis,we evaluated the relationship between CRP and LA thrombus in patients with non-rheumatic AF.

Methods

Study patients

The study population was identi?ed from a retrospective database of278consecutive patients with AF who under-went TEE from October2004to December2008.Patients with rheumatic valvular heart diseases(n=13),prosthetic valve after operation of mitral stenosis(n=11),and those in whom only the aorta was observed because of aortic dissec-tion(n=2)were excluded from this study.In29cases with multiple TEE examinations(total88),only the?rst exam-ination was included in this study.Finally,a total of190 patients(122males,68females,mean age71±10years, range36—95years)with AF were enrolled and analyzed. Among these patients,6patients had infective endocardi-tis,3patients had aortic dissection,24patients had recent embolic events that occurred within2weeks(including acute ischemic stroke).

According to the TEE result,the study patients were divided into2groups depending on the presence(n=19)or absence(n=171)of LA thrombus.In patients with LA throm-bus,10patients had recent embolic events that occurred within2weeks(including acute ischemic stroke).

In addition,patients treated with warfarin therapy[the target prothrombin time-international normalized ratio(PT-INR)value of between2.0and3.0for patients aged<70 years or PT-INR value of between1.6and2.6for patients aged≥70years][11,12]for more than3weeks at the time of TEE(n=73,38.4%)were also divided into2groups,with (n=8,11.0%)and without(n=65,89.0%)LA thrombus. Transthoracic echocardiography(TTE)

All echocardiographic examinations were performed by using Sonos7500(Philips Ultrasound,Bothell,WA,USA)with an S3probe.All subjects underwent a standard transthoracic 2dimensional(2D)and Doppler echocardiographic examina-tions.In addition to routine conventional echocardiographic indices,we measured LA http://www.wendangku.net/doc/c953868683d049649b665840.html volume was measured by the prolate-ellipsoid method,LA volume was calculated as reported previously[13—15].

Transesophageal echocardiography

A T6H probe was used for2D TEE images by using Sonos7500 (Philips Ultrasound).In TEE,the following features were speci?cally assessed:(1)presence or absence of thrombus in the LA or LA appendage(LAA);(2)presence or absence of SEC within the LA or LAA;(3)peak emptying velocity of the LAA;(4)presence or absence of signi?cant(≥moderate) mitral regurgitation(MR).

Thrombus were de?ned as highly echogenic masses adja-cent to the endocardial surface and clearly differentiated from normal structures such as the pectinate muscles.SEC was de?ned as slowly swirling,smoke-like echoes inside the LA or LAA.Gain was continuously adjusted to ensure good visualization and to avoid noise artifacts.The LAA peak emp-tying velocity was obtained by Doppler echocardiography. T wo experienced cardiologists interpreted the TEE blinded to the laboratory data.

Data collection

In each patient,the following information had been col-lected as the initial clinical parameters:gender,age,body mass index(BMI),type of antithrombotic therapy(war-farin,heparin,aspirin,or ticlopidine),coexisting conditions including valvular heart disease which includes signi?cant MR,aortic valve regurgitation and aortic valve steno-sis,ischemic heart disease,hypertrophic cardiomyopathy, dilated cardiomyopathy,hypertensive heart disease(HHD), congenital heart disease,hypertension,diabetes mellitus, and hyperlipidemia.Lone AF was de?ned as AF occurring in the absence of structural heart disease and hypertension under the age of65years.

Blood samples

Blood samples were taken within1week before the TEE examination.In our hospital,laboratory data including CRP were measured routinely before TEE examination.The serum CRP was measured by latex nephelometry(LT Auto Wako CRP,Osaka,Japan).We used latex as the reagent and Hitachi7500analyzer(Hitachi,T okyo,Japan)as the mea-surement system.The lowest detection CRP limit of this test was<0.02mg/dl.After blood samples were taken,medica-tions including anticoagulation were not changed until TEE examination was performed.

Statistical analysis

Data are expressed as mean value±SD or as median value with interquartile range.Differences in clinical features and plasma markers between patients with and without LA thrombus were evaluated with an unpaired Student t-test for normally distributed continuous variables,Mann—Whitney U-test for nonparametrically distributed continuous vari-ables,and chi-square tests for categorical variables.Factors signi?cantly associated with LA thrombus on univariate analysis(p<0.05)were entered into a stepwise logistic regression analysis to determine independent associates of LA thrombus.Statistical analyses were done with StatView 5.0software(SAS Institute,Cary,NC,USA).A p-value of <0.05was considered statistically signi?cant.Inter-and intra-observer agreements for the detection of LA throm-bus was assessed by using kappa statistics.A kappa index above0.8was considered to indicate very good agree-ment.

120

T .Maehama et al.

Table 1

Clinical characteristics and research indices in patients with and without left atrial (LA)thrombus.

LA thrombus (?)

LA thrombus (+)p N

171

19

Age (years)70.9±9.875.4±10.10.06Male (%)

63.7

68.4

0.69Body mass index (kg/m 2)22.8±3.522.5±3.20.68Smoker (%)

36.834.50.84Diabetes mellitus (%)22.242.10.09Hypertension (%)62.089.50.02Hyperlipidemia (%)22.242.10.09ACEI/ARB (%)

33.947.40.24Warfarin (≥21days)(%)9.411.00.73Aspirin (%)22.836.80.26Ticlopidine (%) 3.521.10.01Statin (%)

18.131.60.22Ischemic heart disease (%)10.515.80.45Dilated cardiomyopathy (%)

2.30.0 1.00Hypertrophic cardiomyopathy (%) 6.4 5.3 1.00Hypertensive heart disease (%)16.46

3.2<0.01Congenital heart disease (%) 3.50.0 1.00Valvular heart disease (%)45.021.10.04Lone atrial ?brillation (%) 2.9

0.0

1.00White blood cells (/?l)6225±21957824±40410.05Red blood cells (×104/?l)417±622447±750.05Hematocrit (%)39.8±7.541.9±5.80.08Platelet (×104/?l)20.0±5.620.1±6.10.72PT-INR 1.7±0.8 1.7±0.60.46APTT (s)

36.2±14.734.8±12.30.64Creatinine (mg/dl)

0.93±0.50

0.98±0.27

0.11C-reactive protein (mg/dl)0.13(0.05—0.72)0.90(0.33—2.72)<0.01T otal-cholesterol (mg/dl)182.4±42.0196.6±59.20.65Triglycerides (mg/dl)105.7±60.5104.9±67.30.57LDL-cholesterol (mg/dl)109.5±33.5117.9±50.30.52HDL-cholesterol (mg/dl)

48.6±15.8

49.2±16.3

0.95

Values are mean ±SD,median (interquartile range),or percentage.ACEI,angiotensin-converting enzyme inhibitors;ARB,angiotensin

II receptor blocker;PT-INR,prothrombin time-international normalized;APTT ,activated partial thromboplastin time;LDL,low density lipoprotein;HDL,high density lipoprotein.

Results

Systemic inflammation and left atrial thrombus in patients with non-rheumatic atrial fibrillation.

LA thrombus was detected in 19of 190patients (10%).T able 1summarizes the clinical characteristics of patients with and without LA thrombus.There were signi?cant dif-ferences in HT ,ticlopidine,HHD,valvular heart disease,and CRP between the 2groups.Duration and intensity [PT-INR and activated partial thromboplastin time (APTT)]of anticoagulation therapy were not different between the 2groups.

Fig.1shows a box plot of CRP in patients with and without LA thrombus.CRP in patients with LA thrombus was signif-icantly higher than in patients without LA thrombus [0.90(0.33—2.72)vs.0.13(0.05—0.72)mg/dl,p <0.01].

T able 2shows the TTE and TEE ?ndings.There were signif-icant differences in LA dimension,intraventricular septum,and posterior wall thickness between the 2groups.In addi-tion,in patients with LA thrombus,the LAA velocity was signi?cantly lower and signi?cant MR was less frequently observed than in patients without LA thrombus.In this study ,SEC was found in all patients with LA thrombus.The kappa statistic for inter-and intra-observer agreements for LA thrombus by TEE were 0.94and 1.00,respectively .

By multivariate analysis,HHD (p <0.01),ticlopidine (p =0.01),and CRP (p =0.03)were independent clinical pre-

dictors of LA thrombus (T able 3).According to the receiver operating characteristic (ROC)analysis,a cut-off CRP value for identifying LA thrombus was 0.21mg/dl (sensitivity:84%,speci?city:60%,positive predictive value:19%,and negative predictive value:97%)(Fig.2).

Figure 1Comparison of C-reactive protein (CRP)between patients with and without left atrial (LA)thrombus.

In?ammation and left atrial thrombus

121

Table 2

Findings on transthoracic echocardiography and transesophageal echocardiography .

LA thrombus (?)

LA thrombus (+)p

TTE ?ndings

LA dimension (cm) 4.5±0.8 4.8±0.90.04LA volume (ml)70.7±58.170.9±36.70.53E prime (cm/s)

7.0±2.5 6.8±1.10.58Intra ventricular septum (cm) 1.1±0.2 1.4±0.4<0.01Posterior wall (cm) 1.1±0.2 1.3±0.3<0.01L VDd (cm) 4.7±0.8 4.6±0.90.63L VDs (cm)

3.2±0.9 3.1±1.20.39Ejection fraction (%)57.4±12.25

4.2±1

5.40.56TEE ?ndings

Spontaneous echo contrast (%)26.9

100.0

<0.01LAA velocity (cm/s)36.7±21.018.3±5.9<0.01Signi?cant MR (%)

33.7

10.5

0.04

LA,left atrium;TEE,

transesophageal echocardiography;TTE,transthoracic echocardiography;L VDd,left ventricular diastolic dimension;L VDs,left ventricular systolic dimension;LAA,left atrial appendage;MR,mitral regurgitation.

Table 3Multivariate analysis of characteristics and C-reactive protein levels.

Odds ratio (95%CI)

p Hypertensive heart disease 7.855(2.513—24.554)<0.01C-reactive protein 1.215(1.025—1.439)0.025Ticlopidine

7.214(1.537—33.869)0.012Signi?cant mitral regurgitation 0.605(0.063—5.822)0.663Valvular heart disease 0.667(0.107—4.164)

0.664

Among the patients who were receiving warfarin therapy at the time of TEE (n =77),CRP was also signi?cantly higher in patients with LA thrombus [n =8,0.98(0.67—1.45)vs.0.11(0.04—0.36)mg/dl,

p <0.01](Fig.3)despite similar INR val-ues between the two groups (2.02±0.71vs.2.09±0.78,

Systemic inflammation and left atrial thrombus in patients with non-rheumatic atrial fibrillation.

Systemic inflammation and left atrial thrombus in patients with non-rheumatic atrial fibrillation.

Figure 2Receiver operating characteristics curve to deter-mine the cut-off value of C-reactive protein for left atrial thrombus detection by transesophageal echocardiography .

p =0.92).Optimal anticoagulation (de?ned as PT-INR value of between 2.0and 3.0for patients aged <70years or PT-INR value of between 1.6and 2.6for patients aged ≥70years)[11,12]was not achieved in 19patients (25%),3(16%)in patients with LA thrombus and 16(9%)in patients without LA thrombus.

According to the ROC analysis,a cut-off CRP value for identifying LA thrombus in patients receiving warfarin therapy was 0.62mg/dl (sensitivity:88%,speci?city:81%,

Figure 3Comparison of C-reactive protein (CRP)between warfarin-treated patients with and without left atrial (LA)thrombus.

122T.Maehama et al.

positive predictive value:35%,and negative predictive value:98%).

On the other hand,among the patients who were receiv-ing heparin therapy(n=70,36.8%),LA thrombus was found in10patients.CRP showed a trend toward being higher in patients with LA thrombus than those without[0.78 (0.26—4.81)vs.0.17(0.08—0.53)mg/dl,p=0.03]despite similar APTT values between the two groups(38.4±14.7 vs.38.0±15.6s,p=0.82).

Repeated TEE examinations were performed in10of19 patients(53%)with LA http://www.wendangku.net/doc/c953868683d049649b665840.html thrombus resolved in 4patients,whereas LA thrombus persisted in the remain-ing6patients.The baseline CRP at the time of the?rst TEE was comparable between patients whose LA thrombus disappeared and remained.During follow-up,CRP showed

a trend toward decrease in both groups[resolved group:

0.47(0.15—1.06)to0.20(0.04—0.36)mg/dl,p=0.28,per-sisted group:1.24(0.61—4.26)to0.77(0.25—1.24)mg/dl, p=0.25].On the other hand,PT-INR signi?cantly increased in patients with resolved LA thrombus(1.51±0.34vs.

2.63±0.80,p=0.03),but not in patients with persistent LA thrombus(1.92±0.80vs.2.26±0.73,p=0.48).

T wenty-nine(15%)of190patients had evidence of in?am-matory diseases that could explain a higher CRP.Fourteen patients had infectious diseases(infective endocarditis, pneumonia,sepsis,and infectious arthritis)and15patients had other systemic in?ammatory diseases(rheumatoid arthritis,hyperthyroidism,aortitis,glomerulonephritis,car-cinoma,and appendicitis).After excluding these patients, CRP was still signi?cantly higher in patients with LA throm-bus than in patients without LA thrombus[0.65(0.26—1.12) vs.0.12(0.04—0.42)mg/dl,p<0.01].

Discussion

T o the best of our knowledge,this is the?rst study demon-strating the relationship between systemic in?ammation and LA thrombus in patients with non-rheumatic AF.The predilection of LA thrombus formation in AF patients has long been known.However,the pathogenesis of auricular thrombosis has not been entirely speci?ed yet.Virchow identi?ed a triad of components implicated in the process of thrombosis[16]:abnormal conditions of blood?ow, vessel wall damage,and abnormal blood constituents.In AF,there are variable relations to these three compo-nents:(1)LAA velocity;(2)atrial endothelial cells;and (3)prothrombotic state.Previous studies have suggested an association between decreased blood?ow in the LAA as demonstrated by reduced LAA?ow velocities and the loss of atrial contraction in AF[17,18].Also,the presence of SEC was related to reduced blood?ow velocity in the LAA[19]and could be an independent predictor of LA thrombus[20,21].Furthermore,previous studies have demonstrated that SEC was a predictor of thromboembolic events in future[20,22].The CHADS2[Congestive heart failure,Hypertension,Age,Diabetes,Stroke(Doubled)] score is widely used as a simple and reliable clinical score to identify those with high likelihood of ischemic stroke among patients with AF[23].In fact,HHD was indepen-dently associated with LA thrombus in our present study population.Although previous studies have suggested that LA thrombus was more frequently found in patients with low left ventricular(L V)ejection fraction[24,25],our data did not support these previous reports,possibly because of small sample size.Our study population mainly consisted of patients with preserved L V systolic function and therefore did not show impact of L V systolic function on LA thrombus formation.

In our present study,incidence of signi?cant MR in the LA thrombus group was signi?cantly lower than in patients without LA thrombus,concordant with previous reports.Pre-vious studies suggested that signi?cant MR may be protective against the formation of SEC/LA thrombus[26,27].

A signi?cant difference was present between LA throm-bus and ticlopidine.This was an unlikely?nding that may have been due to chance alone,considering the small num-ber of patients who were on ticlopidine.

Several studies demonstrate that patients with AF show signi?cant increases in plasma?brinogen and D-dimer levels, suggesting the presence of a hypercoagulable or pro-thrombotic state[28—31].In this study,plasma D-dimer level was measured only in70patients(37%)at the time of TEE.Plasma D-dimer levels were signi?cantly higher in patients with LA thrombus than in those without LA throm-bus[2.20(1.20—8.15)vs.0.50(0.50—1.50)?g/ml,p<0.01].

In addition,a previous study has demonstrated that there is a possible link between CRP and deep vein thrombosis [32].Therefore,CRP may play some role in LA throm-bus formation.Furthermore,CRP has been suggested as a biomarker to predict cardiovascular events in apparently healthy subjects as well as patients with coronary artery dis-ease or valvular heart disease[33,34].However,the exact mechanisms by which CRP affects cardiovascular disease are still poorly understood and controversial.

In the present study,we found that elevated CRP was independently associated with the presence of LA thrombus. Our?ndings are consistent with those of previous studies reporting associations between in?ammation and coagula-tion[35,36].It has been reported that CRP promotes platelet adhesion to endothelial cells and emphasize the possible role of CRP in linking in?ammation and thrombosis and provide a potential mechanism for the high incidence of vascular events associated with high CRP level[37].Fur-thermore,a recent report from the Stroke Prevention in Atrial Fibrillation(SPAF)-III study demonstrated that CRP was positively correlated to stroke risk and related to stroke risk factors and prognosis in880patients with AF[38].Our present results may explain the possible link between stroke risk and systemic in?ammation in patients with AF.

An epidemiological study as well as a large-scale ran-domized trial consistently demonstrated that the incidence of stroke in patients with AF is related to the size of the LA[39,40].Morphologic changes of the LA endocardial mus-cle have also been demonstrated in patients with AF[41]. As mentioned,endothelial cells are known to modulate thrombogenesis[39].Therefore,it is possible that some pro-thrombotic alterations in the endocardium may occur during the process of structural remodeling in the LA wall.Yaron et al.have shown that CRP directly affected the endothelial phenotype promoting thrombosis[37].Therefore,in addi-tion to the impact of the LA enlargement,CRP may modulate LA endothelial function leading to thrombogenic status in patients with AF.

In?ammation and left atrial thrombus123

Acute embolic events may also be related to elevated CRP levels.In this study,24(13%)of190patients had recent embolic events that occurred within2weeks.Among these patients,10had LA thrombus.After excluding these patients with recent embolic events,CRP was still signi?cantly higher in patients with LA thrombus than in patients without LA thrombus[0.90(0.50—1.24)vs.0.13(0.05—0.49)mg/dl, p<0.01].

The ef?cacy of oral anticoagulant therapy in reducing the risk of thromboembolic events has been demonstrated in patients with AF.T o optimize the intensity of anticoagula-tion,as indicated by the INR,a target INR needs to achieve the best balance between the prevention of thromboem-bolic events and the occurrence of bleeding complications [42—44].Interestingly,among our study patients on war-farin,INR value did not differ between patients with and without LA thrombus.In fact,there were some cases with LA thrombus even under an acceptable INR value as recom-mended by guidelines.In addition,there was no correlation between CRP and INR(r=0.16,p=0.73).Therefore,in?am-mation may be related to LA thrombus independent of anticoagulation states.A multicenter,prospective and ran-domized study from Japan demonstrated that low intensity warfarin treatment(INR1.5—2.1)for prevention of stroke recurrence was safer than conventional intensity treatment (INR 2.2—3.5)in the elderly[11].Yasaka et al.demon-strated a sharp rise in the incidence of severe hemorrhage in INR≥2.6and reported that most patients suffering severe hemorrhage were elderly[12].Therefore,an INR value of between1.6and2.6seems optimal to prevent major ischemic or hemorrhagic events in elderly Japanese non-valvular AF patients.However,we found that,some cases, even if they had maintenance of the INR within the range which guidelines recommended,had complicated LA throm-bus.In such cases,CRP levels were signi?cantly higher than in those without LA thrombus.Therefore,presence of in?ammation as evident by high CRP level may also help stratify high-risk patients for LA thrombus formation and possibly stroke and peripheral embolism in non-rheumatic AF.In this study,we identi?ed the cut-off CRP value for identifying LA thrombus as0.21mg/dl.In patients receiv-ing warfarin therapy,the cut-off CRP value was0.62mg/dl. Based on our results,the INR value alone may not be enough to predict LA thrombus formation among patients with high CRP.Although LA thrombus resolved in4of10patients who underwent serial TEE examination,CRP level did not signif-icantly change in these patients.The small sample size and a difference in intensity of anticoagulation possibly explain the lack of relationship between serial changes in CRP and LA thrombus.

Limitations

First,this was a single-center retrospective study per-formed in a relatively small number of patients.Second, antithrombotic therapies were not randomized.The formation of LA thrombus is critically dependent upon anticoagulation status and anticoagulation duration.Third, incidence of LA thrombus in patients with recent embolic events may be underestimated because LA thrombus had already been embolized and thus disappeared.Fourth,although LA thrombus was related to high CRP level,causal relationship between prothrombotic state and in?ammation is unclear.In addition,although we found a cut-off CRP value for identifying LA thrombus,in?ammation is not the only predictor of LA thrombus.Therefore,a cut-off CRP value may not be used for predicting LA thrombus but for excluding LA thrombus.Finally,it is unknown whether our present results can be applicable to all patients with AF. Conclusion

Systemic in?ammation is related to LA thrombus formation in patients with non-rheumatic AF.Our results indicate that presence of systemic in?ammation as evident by high CRP level may help stratify high-risk patients for LA thrombus formation and possibly stroke and peripheral embolism in non-rheumatic AF.

Disclosures

None.

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