atrial fibrillation ( af ) is the most common type of arrhythmia in clinical practice . af has a considerable adverse impact on the quality of life of patients and is associated with increased comorbidity and mortality . at present , recent studies have revealed a substantial link between af and inflammation [ 25 ] . in addition , there is further evidence revealing the association between inflammatory factors and left atrial diameter ( lad ) in af . recently identified as a member of the semaphorin protein family , semaphorin 4d ( sema4d ) has been shown to play important roles in neurogenesis , immune response , angiogenesis , and tumor metastasis . once sema4d is activated in inflammatory cells , such as macrophages , a molecular of 120 kda called soluble sema4d ( ssema4d ) is shed from the cell membrane and can be detected in the circulating blood . recent studies have confirmed the role of sema4d as an important regulator of platelet activation and blood coagulation . previous studies demonstrated that serum ssema4d level was associated with the atherosclerotic disease . in af , the stasis and disturbance of blood inside the atria will lead to the mural thrombosis inside cardiac chambers and may contribute to the ischemic stroke as a result of embolization . of note , thus , we performed this study to assess the association between serum ssema4d and af in chinese patients . established risk factors were also measured to evaluate the role of ssema4d as an independent risk factor for af . in addition , we also tested the hypothesis that ssema4d is linked to atrial remodeling . a total of 113 hospitalized patients in the second affiliated hospital of soochow university from october , 2013 to february , 2015 were enrolled in the current study . diagnosis of af was confirmed according to the patient interview , past medical history and electrocardiogram . diagnostic criteria are based on the 2013 american heart association ( aha ) guideline for af . paroxysmal af was defined when recurrent af terminates spontaneously or with intervention within 7 days of onset . persistent af was determined when af continues over 7 days or requires either pharmacological or electrical cardio - conversion to restore sinus rhythm . af , which continues for more than 6 months and/or fails to be converted into sinus rhythm for at least one attempt was defined as permanent af . in summary , there were 56 patients with paroxysmal af , 57 subjects with non - paroxysmal ( including persistent and permanent ) af and another 55 patients without af as a control group . exclusion criteria were valvular heart disease , acute coronary syndrome , acute left heart failure , infection , administration of glucocorticoids within 3 months , major trauma and operation , autoimmune disease , rheumatic activities , severe hepatic or renal dysfunction , hyperthyroidism , and hematological disease . the current study conformed to the principles of the declaration of helsinki and the study protocol was approved by the ethic committee of the second affiliated hospital of soochow university . clinical characteristics were obtained from all subjects on admission , such as age , gender , height , weight , heart rate , past medical history , history of cerebral embolism , cha2ds2vasc score and medication including beta - blockers , amiodarone and anticoagulant medicines . peripheral venous blood were obtained from each patient upon admission and stored in edta anticoagulation vacuum tubes . after immediate centrifugation at 3,000 g for 10 minutes , serum samples were kept at 80c . assessment of ssema4d concentration was conducted using enzyme - labeled immunosorbent assay ( elisa ) kit ( xinle co. ltd . , images and videos were captured at left ventricular long axis and apex quad - chamber view using the vivid 7 station ( ge company , usa ) . data analysis was performed using the spss 17.0 software ( chicago , il , usa ) . one - way anova with subsequent turkey s post - hoc test was used to compare the difference among multiple groups . for data without normal distribution , categorical data was expressed as percentage and compare between groups was carried out using kappa test . multivariate logistic regression using backward method was applied to evaluate the impact of different factors on the risk of af . a total of 113 hospitalized patients in the second affiliated hospital of soochow university from october , 2013 to february , 2015 were enrolled in the current study . diagnosis of af was confirmed according to the patient interview , past medical history and electrocardiogram . diagnostic criteria are based on the 2013 american heart association ( aha ) guideline for af . paroxysmal af was defined when recurrent af terminates spontaneously or with intervention within 7 days of onset . persistent af was determined when af continues over 7 days or requires either pharmacological or electrical cardio - conversion to restore sinus rhythm . af , which continues for more than 6 months and/or fails to be converted into sinus rhythm for at least one attempt was defined as permanent af . in summary , there were 56 patients with paroxysmal af , 57 subjects with non - paroxysmal ( including persistent and permanent ) af and another 55 patients without af as a control group . exclusion criteria were valvular heart disease , acute coronary syndrome , acute left heart failure , infection , administration of glucocorticoids within 3 months , major trauma and operation , autoimmune disease , rheumatic activities , severe hepatic or renal dysfunction , hyperthyroidism , and hematological disease . the current study conformed to the principles of the declaration of helsinki and the study protocol was approved by the ethic committee of the second affiliated hospital of soochow university . clinical characteristics were obtained from all subjects on admission , such as age , gender , height , weight , heart rate , past medical history , history of cerebral embolism , cha2ds2vasc score and medication including beta - blockers , amiodarone and anticoagulant medicines . peripheral venous blood were obtained from each patient upon admission and stored in edta anticoagulation vacuum tubes . after immediate centrifugation at 3,000 g for 10 minutes , serum samples were kept at 80c . assessment of ssema4d concentration was conducted using enzyme - labeled immunosorbent assay ( elisa ) kit ( xinle co. ltd . , images and videos were captured at left ventricular long axis and apex quad - chamber view using the vivid 7 station ( ge company , usa ) . data analysis was performed using the spss 17.0 software ( chicago , il , usa ) . one - way anova with subsequent turkey s post - hoc test was used to compare the difference among multiple groups . for data without normal distribution , categorical data was expressed as percentage and compare between groups was carried out using kappa test . multivariate logistic regression using backward method was applied to evaluate the impact of different factors on the risk of af . there are no substantial differences among the 3 groups in age and gender ( p>0.05 ) . in a total of 113 patients with af , there were 12 patients with a history of cerebral embolism , including 4 patients with paroxysmal af and 8 patients with non - paroxysmal af . the serum ssema4d level in patients with af is significantly increased compared with the control group ( 8.502.19 ng / ml and 9.302.28 ng / ml vs. 6.561.27 ng / ml , p=0.032 ) . serum ssema4d concentrations were elevated in patients with non - paroxysmal af compared to those with paroxysmal af ( 9.302.28 ng / ml vs. 8.502.19 ng / ml , p<0.001 ) ( table 2 ) . interestingly , the lads of the af group was significantly greater compared to the control group ; subgroup analysis showed that the lads in non - paroxysmal af patients were significantly higher compared to those with paroxysmal af ( 54.098.93 mm , 44.367.60 mm vs. 38.157.11 mm , p<0.001 ) . accordingly , patients with af had a higher coagulation state compared with the control group ( p<0.001 ) . we took lad as the independent variable and took ssema4d as the dependent variable , then got the following related scatter diagram ( figure 1 ) . multivariate logistic regression analysis showed that serum ssema4d [ odds ratio ( or ) : 1.543 , 95% confidence interval ( ci ) : 1.083~2.198 , p=0.016 ] , lad ( or : 1.186 , 95% ci : 1.080~1.301 , p<0.001 ) , male ( or : 6.368 , 95% ci : 1.658~24.458 , p=0.007 ) , hr ( or : 1.050 , 95% ci : 1.006~1.096 , p=0.025 ) , hypertension ( or : 27.878 , 95% ci : 3.916~198.457 , p=0.001 ) and chd ( or : 5.967 , 95% ci : 1.464~24.318 , p=0.013 ) were significantly associated with af ( table 5 ) after adjustment for established risk factors including age , gender , height , weight and medication including beta blockers , amiodarone and anticoagulant drugs . there are no substantial differences among the 3 groups in age and gender ( p>0.05 ) . in a total of 113 patients with af , there were 12 patients with a history of cerebral embolism , including 4 patients with paroxysmal af and 8 patients with non - paroxysmal af . the serum ssema4d level in patients with af is significantly increased compared with the control group ( 8.502.19 ng / ml and 9.302.28 ng / ml vs. 6.561.27 ng / ml , p=0.032 ) . serum ssema4d concentrations were elevated in patients with non - paroxysmal af compared to those with paroxysmal af ( 9.302.28 ng / ml vs. 8.502.19 ng / ml , p<0.001 ) ( table 2 ) . interestingly , the lads of the af group was significantly greater compared to the control group ; subgroup analysis showed that the lads in non - paroxysmal af patients were significantly higher compared to those with paroxysmal af ( 54.098.93 mm , 44.367.60 mm vs. 38.157.11 mm , p<0.001 ) . accordingly , patients with af had a higher coagulation state compared with the control group ( p<0.001 ) . we took lad as the independent variable and took ssema4d as the dependent variable , then got the following related scatter diagram ( figure 1 ) . multivariate logistic regression analysis showed that serum ssema4d [ odds ratio ( or ) : 1.543 , 95% confidence interval ( ci ) : 1.083~2.198 , p=0.016 ] , lad ( or : 1.186 , 95% ci : 1.080~1.301 , p<0.001 ) , male ( or : 6.368 , 95% ci : 1.658~24.458 , p=0.007 ) , hr ( or : 1.050 , 95% ci : 1.006~1.096 , p=0.025 ) , hypertension ( or : 27.878 , 95% ci : 3.916~198.457 , p=0.001 ) and chd ( or : 5.967 , 95% ci : 1.464~24.318 , p=0.013 ) were significantly associated with af ( table 5 ) after adjustment for established risk factors including age , gender , height , weight and medication including beta blockers , amiodarone and anticoagulant drugs . theories including ion channel regulation , structural or electrical remodeling and inflammation have been proposed as a potential basis for the onset or persistence of af . spectacularly , recent years have seen increasing evidence about the association between inflammation and af . inflammatory factors , such as hs - crp , tnf - alpha , il-2 , il-6 , il-8 , are considered to be closely associated with the onset , persistence and recurrence of af . initially identified in t lymphatic cells , this molecular exerts a variety of biological functions . it can bind to plexin b1 and cd72 , which are known as receptors of sema4d , and activate signals through multiple pathways including tkr , rhogtp , r - ras , etc . sema4d expression has been confirmed in several cell types , such as t - cells , b - cells , nk cells , neutral granule cells , mononuclear cells , dendrite cells , macrophages , and bone marrow cells . stimulation of these cells may lead to the cleavage of sema4d , releasing a soluble exodomain fragment called ssema4d . subsequently , this fragment will be shed from the cell surface into the blood stream and readily detected in the circulating blood . the underlying mechanism may involve inflammation , in which the activation of the inflammatory cells promotes the activation and shedding of sema4d . we hypothesized that sema4d may be the missing link between inflammation and af . in af , the stasis of blood within recent studies by zhu l. et al . demonstrated that sema4d plays an important role in platelet activation . moreover , increased cleavage and expression of sema4d have been seen in atherosclerotic disease including coronary heart disease and carotid artery stenosis . accordingly , we demonstrated that sema4d is increased in af , which is also considered to be a thrombogenic disease . a growing number of studies demonstrated that atrial remodeling plays an important role in occurrence , persistence and recurrence of af . inflammation is considered to modify the progress of the electrical , structural and neural remodeling of the atria . pathologically , atrial remodeling is reflected by gross enlargement of atrial chambers , super - microstructural change of atrial cardiomyocytes and atrial fibrosis . af can lead to myocardial ischemia , which may further induce the unbalance between inflammatory factors and their inhibitors . over activated inflammation may lead to the onset of af . as a result of hypertension or aging , the intra atrial pressure may increase and the atria will be enlarged , giving rise to regional pressure increment of atrial wall and result in heterogeneity of focal atrial refractory period . this is the fundamental for the generation of chaotic re - entries which can induce subsequent fibrillation activity in the atria . anatomically , atrial remodeling is a gradual process , which may progressively modify the structure of atria , causing the enlargement and dilation of atria , reflected by an elevation of lad seen in echocardiography . our study demonstrated that patients with persistent af have significantly higher lad compared with those with paroxysmal af or placebo , while no considerable difference was found between the last two groups . in addition , the lad in patients with af is positively correlated with ssema4d level . on the other hand , the persistence of af itself may alternatively contribute to the enlargement of atria by increasing activation of sema4d . the major limitation of the study is that this is a retrospective study , which included rather small sample number of the patients from a single center . in addition , we could not further completely separate the subgroup of persistent af from permanent , and accordingly , we could not further explain whether there is a difference between these two groups . therefore , it is needed to a larger sample and more detailed study to evaluate the expression level of ssema4d in patients with different types of af . , ssema4d may regulate the occurrence and persistence of af as well as atrial remodeling via inflammatory pathways .
backgroundthe aim of this study was to evaluate the serum soluble semaphorin 4d ( ssema4d ) in patients with atrial fibrillation and to investigate the relationship of serum ssema4d with left atrial diameter ( lad).material / methodswe studied a total of 113 patients who were subdivided into paroxysmal and non - paroxysmal ( included persistent and permanent ) atrial fibrillation groups , respectively . 
 another 55 subjects without atrial fibrillation were enrolled as the healthy control group . 
 serum levels of soluble semaphorin 4d ( sema4d ) were measured in all subjects using the enzyme - labeled immunosorbent assay method . 
 we also evaluated the coagulation parameters and left atrial diameters.resultspatients with paroxysmal and non - paroxysmal atrial fibrillation had significantly higher ssema4d level compared with controls ( 8.502.19 ng / ml and 9.302.28 ng / ml vs. 6.561.27 ng / ml , p<0.05 ) . 
 serum ssema4d concentrations were elevated in patients with non - paroxysmal atrial fibrillation compared to those with paroxysmal atrial fibrillation ( p<0.001 ) . 
 the level of ssema4d was positively correlated with lad ( r=0.606 , p<0.001 ) . 
 multivariate logistic regression analysis revealed that serum ssema4d , lad , male sex , heart rate , hypertension , and coronary artery disease were associated with atrial fibrillation ( p<0.05).conclusionsserum ssema4d levels are increased in patients with atrial fibrillation and are independently associated with atrial remodeling .