| Atrial fibrillation(AF) is the most common arrhythmia seen in clinical practice, and AF-related abnormalities in hemodynamics and thrombotic events may significantly increase disability and mortality. Atrial structural remodeling, especially fibrosis play an important role in the occurrence and maintenance of AF. But the mechanisms of atrial fibrosis remain poorly understood. Experimental and clinical data collected to date point to a very complex pathophysiology involving a large number of significant players, including oxidative stress, calcium overload, atrial dilatation, micro- RNAs, inflammation, and myofibroblast activation, all of which are likely to be involved one way or another in AF- induced atrial extracellular matrix(ECM) and electrical remodeling. Basic studies have demonstrated that Ang II can promote atrial structural remodeling via the TGF-β1/Smad2/3 signaling pathway. And in the left atrial tissues of AF patients, the expression of the angiotensin II receptor type I(AT1R) is upregulated, and the synthesis of the extracellular matrix increased significantly, suggesting that the AT1 R is associated with atrial fibrosis and AF. There is evidence showing that tumor necrosis factor receptor associated factor 6(TRAF6) / TGF-β-associated kinase 1(TAK1) plays a key role in the activation of TGF-β1/non-Smad signaling pathway. Our previous studies have found that TRAF6/TAK1 signaling pathways participated in AngII-induced fibroblasts proliferation. On the basis of our previous animal studies, we investigated the role of this signaling pathway in atrial fibrosis of patients with chronic AF and rheumatic mitral valve disease(RMVD), and explored the relationship between this signaling pathway and atrial fibrosis in patients with rheumatic heart disease(RHD) and its role in AF after cardiac surgery. Meanwhile, the study explored the relationship among the serum levels of TGF-β1, CTGF and AF, and evaluated the predictive value of the serum levels of TGF-β1 and CTGF for patients with long-standing persistent AF accepted catheter ablation. Our findings may provide evidence useful for the treatment and prevention of AF.Section IObjective: Atrial remodeling is involved in atrial fibrillation(AF), and atrial fibrosis is an important marker of atrial remodeling. On the basis of our previous animal studies of MAPKs/TGF- β1/TRAF6 signaling pathway in atrial fibrosis, we undertook to investigate this signaling pathway in atrial fibrosis of patients with chronic AF(CAF) and rheumatic mitral valve disease(RMVD).Methods: Fifty-six RMVD patients were divided into CAF(course of AF: >12 months) and sinus rhythm(SR) groups. Left atrial appendage tissue was collected during heart surgery, and pathological examination was done to evaluate atrial fibrosis. Protein and m RNA expression of TGF-β1, TRAF6, and connective tissue growth factor(CTGF) and protein expression of phosphorylated MAPKs and TGF-β-activated kinase 1(TAK1) were measured.Results: Histological examination revealed that the severity of atrial fibrosis in CAF patients was significantly higher, m RNA and protein expression of TGF-β1, TRAF6 and CTGF in CAF was significantly increased and the protein expression of phosphorylated MAPKs and TAK1 was significantly increased in CAF compared to SR patients.Conclusion: The MAPKs/TGF-β1/TRAF6 signaling pathway is involved in atrial fibrosis of CAF patients, and TRAF6 may become a new target for the treatment of atrial fibrosis.Section IIObjectives: To explore the relationship between MAPKs/TGF- β1/TRAF6 signaling pathway and atrial fibrosis in patients with rheumatic heart disease(RHD) and its role in atrial fibrillation(AF) after cardiac surgery on the basis of our previous animal study of MAPKs/TGF- β1/TRAF6 signaling pathway in atrial fibrosis.Methods: A total of 57 patients having RHD without a history of AF consented to left atrial biopsy. Histopathology quantified the percentage of fibrosis, and real time PCR and western blot assessed m RNA and protein expression of TGF-β1, TRAF6, and connective tissue growth factor(CTGF) respectively, western blot measured the protein expression of phosphorylated MAPKs and TGF-β-activated kinase 1(TAK1).Results: Eighteen patients developed AF, whereas 39 remained in normal sinus rhythm(NSR). The severity of atrial fibrosis was significantly higher in patients who developed AF versus NSR,m RNA and protein expression of TGF-β1, TRAF6 and CTGF was significantly higher in patients with AF; the protein expression of phosphorylated MAPKs and TAK1 was significantly increased in patients developing AF compared to NSR patients.Conclusion: This demonstrates that the MAPKs/TGF-β1/TRAF6 signaling pathway is involved in the process of atrial fibrosis in patients with RHD which results in the occurrence of AF after cardiac surgery; TRAF6 possibly become a new target spot for inhibiting atrial fibrosis process in the future.Section IIIObjective: To explore the relationship among the serum levels of TGF-β1, CTGF and AF, And to evaluate the predictive value of the serum levels of TGF-β1 and CTGF for patients with long-standing persistent AF accepted catheter ablation.Methods: 92 patients obtained current ablation endpoints with long-standing persistent AF were studied. We collected serum from healthy people as control group according to the ratio of age, sex of the patients with AF accepted catheter ablation. The serum levels of TGF-β1 and CTGF were detected by ELISA. We compared the serum levels of TGF-β1 and CTGF among groups, and explored the relationship between TGF-β1 and CTGF in each group. Logistic regression analysis was performed to identify the independent predictors of AF recurrence.Results: 44 patients suffered AF recurrence(AF recurrence group) and 48 patients were classified as non-AF recurrence group. As compared with control group, the serum levels of TGF-β1 and CTGF were significantly increased in other groups. And the serum levels of TGF-β1 and CTGF serum levels of TGF-β1 was significantly increased in the AF recurrence group as compared with that in the non-AF recurrence group. The serum levels of CTGF was significantly negatively correlated with TGF-β1 in AF recurrence group. In the logistic regression analysis, longer AF duration and increased serum level of TGF-β1 were determinate as the independent predictors of AF recurrence.Conclusion: the serum levels of TGF-β1 and CTGF in patients with long-standing persistent AF were significantly increased. In AF recurrence patients, the serum TGF-β1 levels increased more significantly, and negatively correlated with CTGF levels. Longer AF duration and increased serum level of TGF-β1 were determinate as the independent predictors of AF recurrence. |
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