Europace Advance Access originally published online on January 8, 2008
Europace 2008 10(2):210-214; doi:10.1093/europace/eum284
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ABLATION FOR ATRIAL FIBRILLATION
Prognostic value of plasma soluble CD40 ligand in patients with chronic non-valvular atrial fibrillation
1 Department of Cardiology, Karsiyaka State Hospital, Serinkuyu, Karsiyaka, 35220 Izmir, Turkey; 2 Department of Internal Medicine, Tepecik Training and Research Hospital, Izmir, Turkey; 3 Department of Cardiology, Central Hospital, Izmir, Turkey
Manuscript submitted 1 September 2007. Accepted after revision 5 December 2007.
* Corresponding author. Tel: +90 2323904001; fax: +90 232 3903287.E-mail address: hamzakard{at}yahoo.com
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Abstract |
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Aims: We aimed to clarify whether determination of levels of soluble CD40 ligand (sCD40L) could predict subsequent thrombo-embolic events in patients with non-valvular atrial fibrillation (NVAF).
Methods and results: Forty-four consecutive outpatients (mean age: 58 ± 6 years, 20 male) with chronic NVAF who were not receiving aspirin and had no thrombus or spontaneous echo contrast (SEC) on left atrium (LA) or left atrial appendage (LAA) were included in the study. The patients had no history of an embolic event and were followed up 24 ± 2 months for thrombo-embolic events. sCD40L was determined at the enrollment. All patients were evaluated by means of SEC and thrombus formation by transoesophageal echocardiography at the end of follow-up period. Twelve (27%) patients had SEC and 2 (5%) patients had thrombus on LAA. Ischaemic stroke occurred in 2 (4.5%) patients and transient ischaemic attack developed in 4 (9%) patients during follow-up. sCD40L was significantly higher in patients with LASEC (0.41 ± 0.05 vs. 0.16 ± 0.04 ng/mL, P = 0.02) and embolic events (0.74 ± 0.05 vs. 0.19 ± 0.03 ng/mL, P = 0.001) than in those without. sCD40L levels were significantly related to the LASEC grade (R = 0.377, P = 0.02). In multivariable analysis, while independent variables for SEC or thrombus formation were LA diameter, sCD40L levels, and the duration of AF, independent variables for cerebrovascular events were the existence of SEC or thrombus formation on LAA, and sCD40L level.
Conclusion: Plasma sCD40L may prospectively predict stroke in AF. sCD40L may provide useful marker to identify patients at high thrombo-embolic risk with NVAF.
Key Words: Atrial fibrillation, Embolic event, Thrombus, Soluble CD40 ligand
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Introduction |
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Non-valvular atrial fibrillation (NVAF) is the most common sustained cardiac arrhythmia and is associated with a five-fold increase in stroke risk.1
Embolization of thrombi forming in the left atrium (LA) or left atrial appendage (LAA) is essential for stroke in patients with atrial fibrillation (AF).2 Risk of thrombo-embolic stroke varies widely according to presence or absence of certain clinical and echocardiographic findings3,4 and plasma markers.5,6 However, despite the well-recognized link between cardiac embolism resulting from AF and ischaemic stroke, the mechanism of thrombus formation is still not fully understood. Several studies have shown that AF is accompanied by a hypercoagulative state that may contribute to the development of atrial thrombi and thrombo-embolism.7–10 Thrombosis appears to be intimately related to inflammation, and there is now considerable evidence that AF is associated with an inflammatory state.11 The abnormal inflammatory state may ‘drive’ the prothrombotic state in AF, which may contribute to the increased risk of thrombogenesis and, subsequently, thrombo-embolism.12
Evidence has increasingly emerged that activated platelets play a pivotal role in inflammatory processes as a result of platelet–leukocyte and platelet–endothelium interactions; thus, platelets are important and abundant inflammatory cells per se.13 The CD40–CD40 ligand (CD40L) system has been implicated in the pathophysiology of atherothrombotic complications and prognosis in cardiovascular disease, as well as in the processes of inflammation and thrombosis.14,15 The surface-expressed CD40L is cleaved from the platelets over a period of minutes to hours, subsequently generating a soluble fragment.16 Circulating soluble CD40 ligand (sCD40L) is believed to derive predominantly from activated platelets and, hence, may reflect platelet activation.17 High plasma concentrations of sCD40L were proposed to be associated with increased vascular risk.18–20
Although a marked increase in the levels of inflammatory markers has been identified in the setting of persistent AF, the relationship between proinflammatory and prothrombogenic factors remains unclear, and sCD40L has not yet been assessed in patients with AF prospectively. Whether sCD40L contributes to thrombus formation and stroke/transient ischaemic attack (TIA) in NVAF is not clear, and whether it can be used as a predictor of risk of thrombus formation and stroke in NVAF needs to be clarified. We hypothesized that sCD40L representing platelet activation would be related to the presence of thrombo-embolic events in patients with NVAF. We, therefore, performed a prospective study to clarify whether determination of the sCD40L levels could predict subsequent thrombo-embolic events in patients with NVAF.
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Study population
Forty-four consecutive outpatients (mean age: 58 ± 6 years, 20 male) with chronic asymptomatic NVAF who were not receiving aspirin and had no thrombus or spontaneous echo contrast (SEC) on LA or LAA were included in the study. Seven patients were on warfarin. AF was defined as rapid oscillations or fibrillatory waves varying in size, shape, and timing, and associated with an irregular, frequently rapidly ventricular response. Persistent, chronic AF was confirmed by electrocardiography at least two separate occasions (
6 weeks apart). The patients had no history of an embolic event and were followed up 24 ± 2 months for thrombo-embolic events including clinically evident cerebral infarction, TIA, or embolism of peripheral arteries. Cerebral infarction was defined clinically as a new neurologic deficit lasting >24 h and not attributable to dysfunction of a single cranial nerve, spinal cord, or the peripheral nervous system. TIA was defined as an abrupt onset of a focal neurologic deficit lasting >1 min and <24 h within the territory of a single major brain artery. The diagnosis of peripheral embolism was defined clinically as an abrupt vascular insufficiency of the limbs or internal organs associated with clinical or radiologic evidence of arterial occlusion. The diagnosis of cerebral infarction was confirmed by corresponding positive evidence on computed tomography or magnetic resonance imaging. Stroke risk scores were calculated according to the CHADS2 scheme (congestive heart failure = 1 point, hypertension = 1, age 75 = 1, diabetes mellitus = 1, and prior stroke or TIA = 2).21 Exclusion criteria were as follows, heart failure, coronary artery disease, diabetes mellitus, inflammatory diseases (e.g. infections, autoimmune diseases), malignancies, impaired liver function, renal failure, recent surgery, valvular heart diseases, thyroid dysfunction, previous myocardial infarction or stroke as these disorders might influence platelet activation and the level of sCD40L. Patients who used non-steroidal anti-inflammatory drugs, corticosteroids, or hormone replacement therapy regularly were also excluded. All patients gave informed consent, and the study protocol was approved by the local ethics committee.
Transoesophageal echocardiography
Transoesophageal echocardiography (TEE) was performed at the enrollment to confirm the absence of an LA cavity or appendage thrombus and at the end of follow-up period to detect eventual intracardiac thrombus or SEC in all patients with a 5.0 MHz multiplane probe (Hewlett-Packard Sonos 2500, Andover, MA). LASEC was defined as the presence of smoke-like echo with a characteristic swirling motion in the LA cavity and appendage. LASEC was graded from 0 to 4. Grades 0 and 1 were considered as mild, while grades 2 to 4 were defined as moderate to severe. Atrial thrombus was referred to the presence of a clearly defined intracavitary mass acoustically distinct from the underlying endocardium and not caused by the pectinate ridges of the LAA. Imaging data were recorded on super video home system (VHS) videotapes and were reviewed by two experienced observers blinded for clinical and laboratory data.
Blood sample collection and measurement of plasma sCD40L concentrations
Soluble CD40 ligand was determined at the enrollment in the prospective study. Baseline plasma level of sCD40L was analysed for their association with the risk of subsequent embolic events. Patients were excluded if on aspirin or clopidogrel therapy prior to blood sampling, as the potential impact of these drugs on platelet activity cannot be determined. Drugs other than aspirin and clopidogrel including beta-blockers, calcium channel blockers, digoxin, and any combination of these drugs were considered to be acceptable before blood sampling. Warfarin therapy was also discontinued for 3 to 4 days before blood examinations. Plasma level of sCD40L was determined by ELISA kit (R&D Systems) according to the manufacturer's instructions. The lower limit of detection for the sCD40L assay was 0.016 ng/mL, and the intra-assay and inter-assay coefficients of variation were 7.0 and 9.6%, respectively.
Statistical analysis
Statistical analysis was performed using the SPSS 13.0 statistical package (SPSS Inc., Chicago, IL). Quantitative values were expressed as mean ± standard deviation and qualitative values as percentage. While the 
2 test or Fisher's exact test was used for categorical values, the Student's t-test or Mann–Whitney U-test was utilized to compare the continuous variables as appropriate. Multiple logistic regression analysis was used to determine the significance of dependent variable among multiple independent variables. Correlation analysis was performed by using the Pearson's correlation coefficients. A P-value of <0.05 was considered statistically significant.
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Results |
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Baseline characteristics, clinical and echocardiographic follow-up results of the study population are shown in Tables 1 and 2. Seven patients were receiving warfarin with mean international normalized ratio being 2.1 at the time of enrollment. Twelve (27%) patients had SEC and 2 (5%) patients had thrombus on LAA on TEE (Table 2). All patients who were on warfarin had SEC on TEE at the end of follow-up. Any other reason for cardioembolism was not determined on TEE. Ischaemic stroke occurred in 2 (4.5%) patients with thrombus on TEE and TIA developed in 4 (9%) patients with SEC on TEE during follow-up. sCD40L was significantly higher in patients with LASEC (0.41 ± 0.05 vs. 0.16 ± 0.04 ng/mL, P = 0.02) and embolic events (0.74 ± 0.05 vs. 0.19 ± 0.03 ng/mL, P = 0.001) than in those without (Figure 1). sCD40L was higher in patients with LA thrombus than in those without, but it was not statistically significant (0.73 ± 0.09 vs. 0.32 ± 0.04 ng/mL, P = 0.1). sCD40L levels were significantly related to the LASEC grade (R = 0.377, P = 0.02). The average CHADS2 score was higher in patients with embolic event or echocardiographic evidence of prothrombotic state than in those without (0.6 vs. 0, P = 0.03). In multivariable analysis, while independent variables for SEC or thrombus formation were LA diameter, sCD40L levels, and the duration of AF, independent variables for cerebrovascular events were the existence of SEC or thrombus formation on LAA and sCD40L level (Table3). There was no significant relationship between warfarin use and sCD40L level on univariate analysis.
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Discussion |
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Abnormalities of haemostasis, fibrinolysis, endothelium, and platelets have all been described in AF, which may increase the risk of stroke and thrombo-embolism.8
,22–27 Furthermore, certain indexes of the prothrombotic state have been associated with an increased risk of LAA thrombus and SEC, suggesting an increased risk of thrombo-embolism,28,29 and may even predict future stroke and cardiovascular morbidity/mortality in those with AF.10
Although there appears to be a link between inflammation and AF, one of the key questions is whether the observed inflammation in AF increases the risk of thrombo-embolism as has been demonstrated for atherosclerotic models. Conway et al.29 were the first to confirm this putative link between inflammation and complications of AF. In a small pilot study, they showed that elevated interleukin-6 levels were an independent predictor of the composite of stroke or death among a cohort of AF patients. This observation was complemented by data from Thambidorai et al.30 They showed that risk factors for stroke were greater in patients with elevated high-sensitivity C-reactive protein than in those with normal levels among 104 patients with AF. Hence, there appears to be an established link between inflammation, AF, and thrombosis.
The abnormal platelet activation in NVAF may represent a ‘pre-embolic’ status.31 Studies have shown that in patients with paroxysmal AF, platelet activation takes up to 12 h to be initiated. Sohara et al.32 reported that the levels of beta thromboglobulin, platelet factor 4 and markers of coagulation were significantly higher at 12 h after the onset of AF in patients with paroxysmal AF when compared to the levels 7 days into the sinus rhythm. Platelet activation in AF may be due to AF itself.33 Indeed, platelet activation seems to occur even before the occurrence of SEC in patients with AF34 and is correlated with both SEC and LA thrombus in AF.31,34 Pongratz et al.31 demonstrated that the amount of circulating platelets expressing P-selectin was significantly higher in patients with SEC or LA thrombus in comparison with patients without either of these. Certainly, Heppel et al.34 found raised plasma levels of vWf to be predictive of the presence of LAA thrombus visible by TEE, whereas Fukuchi et al.35 found a significant correlation between the degree of endocardial expression of vWf and the degree of platelet adhesion/thrombus formation in LAA. Furthermore, Goldsmith et al.36 found raised plasma vWf associated with damaged atrial appendage endocardium in patients with mitral valve disease and AF.
It has become clear that besides their role in haemostasis and thrombosis, platelets regulate a variety of inflammatory responses. This is achieved by the regulated expression of adhesive and immune receptors on the platelet surface and by the release of a multitude of secretory products including inflammatory mediators and cytokines, which can mediate the interaction with leukocytes and enhance their recruitment.37 Although a marked increase in levels of inflammatory markers has been identified in the setting of persistent AF, the relationship between proinflammatory and prothrombogenic factors remains unclear, and sCD40L as a prothrombotic and proinflammatory marker has not yet been assessed in patients with AF prospectively.
CD40 ligand is a trimeric, transmembrane protein of the tumor necrosis factor family and, together with its receptor CD40, is an important contributor to the inflammatory processes that lead to atherosclerosis and thrombosis.38 The surface-expressed CD40L is cleaved from the platelets over a period of minutes to hours, subsequently generating a soluble fragment.16 sCD40L is a prothrombotic and proinflammatory marker.38–41 To date three studies were performed to identify the role of CD40L system in AF. Blan et al.42 found that sCD40L was marginally raised in AF and the increase in sCD40L was small when compared to P-selectin and vWf. Hammwöhner et al.43 investigated the effect of platelet CD40L expression and its relation to inflammatory markers in atrial clot formation in patients with persistent AF. They showed the elevation of CD40L expression in patients with AF particularly in patients with atrial thrombi. Furthermore, the amount of platelet CD40L expression remains elevated even five weeks after the successful cardioversion. They concluded that these results may imply an increased risk for atrial thrombus formation. Recently, Lip et al.44 investigated the CD40L and C-reactive protein levels according to the three established stroke risk factors in patients with AF. In this study, while C-reactive protein was positively correlated to stroke risk and related to stroke risk factors and prognosis, results were less clear with sCD40L. sCD40L was not significantly higher in patients with LA thrombus than in those without, due to small number of patients with LA thrombus in our study. However, sCD40L was significantly higher in patients with LASEC and embolic events than in those without. Also, Chello et al.45 provided in vitro evidence that AF results in upregulation of CD40 on atrial endocardium with an increased platelet adhesion, and they showed as well that this prothrombotic state is favourably affected by simvastatin.
Dynamic smoke-like echoes in LA, known as SEC, have been reported to be additional markers of thrombo-embolic risk and represent a pre-embolic status in patients with non-rheumatic AF.46 Though platelets alone did not appear to be echogenic in an in vitro model in contrast to whole blood,47 platelet activation plays an essential role in thrombogenesis, and evidence of increased platelet aggregation was reported in patients with SEC.48 Our study is the first to demonstrate that raised levels of sCD40L can predict thrombus formation and stroke in AF prospectively.
Limitations
The present study has several limitations. First, the sample size of the study was small. Secondly, other inflammatory markers were not measured. Therefore, we cannot comment on the relative value of this biomarker in comparison to others. Finally, our study population has a relatively high-event rate, despite relatively low-risk patients. According to the ACC/AHA/ESC 2006 Atrial Fibrillation guidelines, aspirin or warfarin is recommended for patients with one moderate-risk factor (age 75, hypertension, heart failure, diabetes mellitus or LV ejection fraction 
35%) and aspirin is recommended for patients with no risk factors.49 However, aspirin was not started, as it might influence platelet activation and the level of sCD40L. Of all study population, nine patients had one moderate-risk factor such as hypertension. Two patients out of those nine patients refused warfarine use due to the history of gastrointestinal bleeding. Only seven patients were on warfarin. Remaining patients did not receive any anticoagulant or antiplatelet agent. This might be an explanation of relatively high-event rate in our study.
Clinical implications
In our study, patients with LASEC or an embolic event had significantly higher levels of sCD40L, reflecting an enhanced platelet activation. Plasma sCD40L may prospectively predict stroke in AF. Furthermore, sCD40L may present a target for the development of novel thromboprophylactic agents in AF. Determination of this membrane activation marker may provide a useful marker to identify patients at high thrombo-embolic risk with NVAF. Although our study supports the existence of an association between thrombo-embolic events and sCD40L in AF, there are many issues that require further investigations.
Conflict of interest: none declared.
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