Structural Remodeling And Expression Of Isoforms Of Transforming Growth Factor-beta, Matrix Metalloproteinase-2 And Tissue Inhibitor-2 Of Metalloproteinase In Human Left And Right Atrial Tissue Of Atrial Fibrillation In Patients With Rheumatic Heart Disea

Objective:To study atrial structural remodeling and explore the mRNA expression of transforming growth factor beta-1 (TGFβ1) and beta-2 (TGFβ2), matrix metalloproteinase-2(MMP-2) and tissue inhibitor-2 of metalloproteinase(TIMP-2) in patients with rheumatic heart disease with or without atrial fibrillation. To evaluate the influence of these factors expression on atrial structural remodeling.Methods:Total 39 patients were enrolled,24 with chronic atrial fibrillation (AF) and 15 with sinus rhythm (SR). Left and right atrial appendage tissue samples were obtained from these patients during mitral valve replacement operation. Before operation, all of the patients above underwent echocardiographic evaluation and related clinical data were collected. For each sample, histological examination was performed with routine hematoxylin-eosin, masson and immunohistochemistry staining. We also used histological assessment software to calculate extracellular collagen matrix surface area fraction and quantify the amount of extracellular collagen matrix. TGFβ1,TGFβ2,MMP-2 and TIMP-2 mRNA levels were measured by semi-quantitative reverse transcription polymerase chain reaction techniques.Results:Compared with SR group, Left atrial inner diameter was significantly increased in the patients of the AF group. In HE stain, myocardial hypertrophy, severe myolysis and extensive fibrosis in the interstitial space of the atria were found in AF group. And masson stain showed that mean extracellular collagen volumetric fraction was also significantly higher in either RA or LA of AF group (P<0.05). The typeⅠcollagen protein levels in the LA and RA significantly increased in patients with AF compared with SR (P＜0.05), whereas typeⅢcollagen protein were not significantly altered between two groups. Both in the LA and RA TGFβ1,MMP-2 mRNA levels were significantly increased in patients with AF compared with SR (P＜0.05), whereas TIMP-2 mRNA was down regulated significantly (P＜0.05). TGFβ2 mRNA did not exhibit any significant changes(P>0.05). Conclusions:Chronic atrial fibrillation results in significant pathological alterations in atrial geometry, extracellular matrix and myocytes. Atrial structural remodeling in the artia of patient with AF is characterized by extensive atrial interstitial fibrosis, especially in LA. Atrial structural remodeling may help to promote AF initiation and maintenance. The selective differential changes of TGFβ1,MMP-2 and TIMP-2 could be some important molecular mechanisms of the initiation and maintenance of atrial fibrillation.