| BackgroundAtrial fibrillation(AF)is the most common cardiac arrhythmia of clinic significance.According to a global epidemiological survey of AF,there have been progressive increases in the worldwide prevalence and incidence of AF with significant effects on associated morbidity and mortality.Numerous techniques for rhythm control of AF are available to clinicians,including anti-arrhythmic drug(AAD)therapy,electrical cardioversion,catheter(endocardial)ablation and surgical AF(epicardial)ablation and hybrid approaches.Totally thoracoscopic surgical ablation is a successful minimally invasive treatment for AF,typically for patients with refractory and symptomatic AF.Some recent researches have revealed that epicardial adipose tissue(EAT),as a special cardiac fat,may promote the occurrence and development of AF by interacting with myocardium through fatty infiltration,fibrosis,inflammation and other mechanisms.What's more,EAT thickness or volume can predict the AF recurrence after radiofrequency catheter ablation.Activin A,a member of the transforming growth factor-? superfamily of cytokines,which is composed of disulphide linked dimers of ?-subunits,involves a wide range of biological effects.Similarly,studies have shown that Activin A expression in EAT not only promotes atrial fibrosis,but also is associated with the occurrence and development of AF and can predict the occurrence of AF after cardiac surgery.However,most of the current studies are limited to the correlation between EAT and the recurrence of AF after catheter ablation,while the correlation between EAT and Activin A,and the correlation between Activin A and outcomes of AF after thoracoscopic surgical ablation are still unknown.Objectives1.To clarify the correlation between epicardial adipose tissue Activin A expression and EAT thickness and atrial fibrosis.2.To explore the value of epicardial adipose tissue Activin A expression in predicting the recurrence of atrial fibrillation after thoracoscopic surgical ablation in patients with atrial fibrillation.MethodFrom Jan 2015 to Jan 2018,a total of 160 patients with symptomatic drug refractoryAF,received thoracoscopic surgical ablation in Changzheng Hospital affiliated to Second Military Medical University in China.According to history and electrocardiogram,they were divided into two groups: paroxysmal atrial fibrillation group(PAF)and persistent atrial fibrillation group(PsAF).Baseline characteristics were collected from all patients who met the inclusion criteria after admission,including gender,weight,age,body mass index(BMI),NYHA classification and past history.ECG and transthoracic echocardiography were performed and recorded the echocardiographic data: left atrial diameter(LAD),left ventricular end systolic volume(LVESV),left ventricular end diastolic volume(LVEDV),left ventricular ejection fraction(LVEF),left ventricular posterior wall thickness,ratio of mitral valve to mitral annular peak diastolic velocity(E/e' ratio)and EAT thickness.In the next morning after admission,fasting blood was taken for examination of the liver and kidney function,B-type natriuretic peptide(BNP),C-reactive protein(CRP),blood lipid,electrolyte and other blood parameters.Left atrial appendage and its surrounding epicardial fat tissue were collected during the operation.Fluorescence quantitative reverse transcription-polymerase chain reaction(Q-PCR),Western-Blot(WB)and Immunohistochemistry(IHC)were used to quantify ?-SMA,bFGF,Col I and Col III expression in LAA and Activin A expression in EAT.All patients were followed up for 1 year after ablation.Atrial fibrillation recurrence was defined as rapid atrial arrhythmias(atrial fibrillation,atrial flutter and atrial tachycardia)recorded by electrocardiogram or 24-hour dynamic electrocardiogram lasting more than 30 seconds.Follow-up was conducted in 1 month,3 month,6 month and 12 month after ablation.The follow-up items included symptoms,electrocardiogram and24-hour dynamic electrocardiogram.All data were analyzed with SPSS 25.0 software and differences were considered significant when P<0.05.Results1.Baseline characteristicsAccording to the recurrence of atrial fibrillation during the follow-up period,the patients were divided into two groups: the recurrence group of atrial fibrillation(RAF group,34 cases)and the non-recurrence group of atrial fibrillation(NRAF group,126cases).There were significant differences in CHA2DS2-VASc score,duration of atrial fibrillation and type of atrial fibrillation between the two groups(P < 0.05),but no significant differences in age,sex,BMI,blood lipid,BNP and creatinine(P>0.05).There were no significant differences in intraoperative bleeding,tracheal intubation time,operation time,thoracic drainage,hospitalization days,coronary heart disease,hypertension,stroke and other complications between the two groups(P>0.05).2.Preoperative echocardiographic dataEAT thickness in RAF group was significantly thicker than that in NRAF group[(6.78±0.55)mm vs(5.79±0.59)mm,P<0.01],left atrial diameter was larger than that in NRAF group [(45.56±2.54)mm vs(40.53±4.07)mm,P<0.01],and the ratio of mitral valve to mitral annulus peak velocity in early diastolic phase was higher than that in NRAF group [(15.44±3.69)vs(13.98±3.11),P=0.03].There difference between the two groups regarding left ventricular ejection fraction,left ventricular posterior wall thickness,left ventricular end systolic diameter and left ventricular end diastolic diameter was not statistically significant.(P > 0.05).3.Epicardial adipose tissue Activin A expression3.1 DistributionImmunohistochemistry results showed that there was the expression of Activin A in both groups,while the positive expression was more intensive in RAF group than NRAF group.3.2 Protein expression levelActivin A in protein expression level of RAF group was higher significantly than those of NRAF group [(1.37±0.13)vs(0.95±0.08),P<0.01].3.3 mRNA expression levelThe Activin A expression level of RAF group in EAT was significantly higher than those of NRAF group [(34.52±6.40)vs(26.42±4.09),P<0.01].4.Morphologic alternation of atrial fibrosisMasson's stain showed that the positive expression in atrium of RAF group was muchmore intensive than NRAF group,which manifested with more blue-stained fiber and irregular distribution.In addition,the CVF in atriums of RAF group was higher than that of NRAF group [(43.72±3.04)% vs(32.73±4.17)%,P<0.01].5.Fibrosis parameters expression in atrial myocardium5.1 DistributionImmunohistochemistry results showed that there were the expression of ?-SMA,bFGF,Col ? and Col ? in both groups.?-SMA,bFGF and Col ? expression of RAF group was significantly higher than NRAF group,while the difference was not significant in terms of Col ?.5.2 Protein expression levelProtein expression level of ?-SMA,bFGF and Col ? increased significantly in RAF group [(1.05±0.16)vs(0.64±0.06),P<0.01],[(0.54±0.05)vs(0.29±0.06),P<0.01] and[(0.75±0.07)vs(0.41±0.06),P<0.01],while the Col ? also increased without statistical significance [(1.09±0.17)vs(1.14±0.12),P=0.072].5.3 mRNA expression levelThe mRNA expression level of ?-SMA,bFGF and Col ? in left atrial myocardium of RAF group were higher than that of NRAF group [(3.09±0.30)vs(2.10±0.28),P<0.01],[(0.95±0.10)vs(0.55±0.11),P<0.01] and [(1.34±0.14)vs(0.84±0.16),P<0.01].The expression of Col ? mRNA in the two groups was not statistically significant [(1.21±0.18)vs(1.12±0.26),P=0.074].6.Correlation between Activin A and atrial fibrosisThe expression level of Activin A in EAT was significantly correlated with EAT thickness(r=0.691,P<0.01),CVF(r=0.562,P<0.01),Col I(r=0.655,P<0.01),Col ?(r=0.339,P<0.01),?-SMA(r=0.448,P<0.01)and bFGF(r=0.565,P<0.01).7.Predictors of recurrence after thoracoscopic ablationUnivariate analysis showed that type of AF(HR: 3.292,P=0.001)?duration of AF(HR: 1.068,P=0.001),BMI(HR: 1.147,P=0.034),CHA2DS2-VASc score(HR: 1.325,P=0.023),LAD(HR: 1.364,P<0.01),E/e' ratio(HR: 1.105,P=0.027),EAT thickness(HR:3.974,P<0.01)and Activin A(HR: 1.221,P<0.01)were closely associated with AF recurrence after ablation.multivariate COX regression analysis showed that EAT thickness(HR: 2.944,P=0.008),CHA2DS2-VASc score(HR: 1.442,P=0.030),duration of atrial fibrillation(HR: 1.043,P=0.030),LAD(HR: 1.175,P=0.022)and Activin A(HR: 1.120,P=0.001)were independent risk factors for the recurrence of AF after ablation.8.Subgroup analysis8.1 Persistent atrial fibrillation groupThe recurrence rates were 43.33%(n=13)in PsAF group.EAT was thicker in patients with recurrence than those without [(7.11±0.64)mm vs(6.17±0.57)mm,P<0.01].At a cut-off value of 6.70 mm identified by the ROC curve for predicting recurrence based on EAT thickness.Similarly,the expression of Activin A in patients with recurrence after operation was significantly higher than that in patients without [(37.32±6.44)vs(28.27±4.72),P<0.01].At a cut-off value of 32.36 identified by the ROC curve for predicting recurrence based on Activin A expression.Kaplan-Meier survival analysis found that patients with Activin A expression>32.36 were associated with a higher recurrence rate after surgical ablation(P<0.01).8.2 Paroxysmal atrial fibrillation groupThe recurrence rates were 19.3%(n=21)in PAF group.EAT was thicker in patients with recurrence than those without [(6.57±0.37)mm vs(5.73±0.57)mm,P<0.01].At a cut-off value of 6.15 mm identified by the ROC curve for predicting recurrence based on EAT thickness.Similarly,the expression of Activin A in patients with recurrence after operation was significantly higher than that in patients without [(34.52±6.40)vs(26.42±4.09),P<0.01].At a cut-off value of 30.68 identified by the ROC curve for predicting recurrence based on Activin A expression.Kaplan-Meier survival analysis found that patients with Activin A expression>30.68 were associated with a higher recurrence rate after surgical ablation(P<0.01).Conclusion1.The Activin A expression in EAT was correlated with EAT thickness measured by transthoracic echocardiography before ablation.2.The Activin A expression in EAT was significantly correlated with atrial fibrosis,such as ?-SMA,bFGF,Col I and Col III,implying that Activin A may promote atrial fibrosis and atrial fibrillation.3.The Activin A expression in EAT was an independent risk factor for the recurrence of atrial fibrillation after surgical ablation.Activin A can be a useful parameter in predicting AF recurrence after thoracoscopic surgical ablation. |
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