Atrial fibrosis and atrial fibrillation: The role of the TGF-β1 signaling pathway

Introduction: Atrial Fibrillation (AF) is associated with remodeling of the atrial tissue, which leads to fibrosis that can contribute to the initiation and maintenance of AF. Delayed- Enhanced Cardiac Magnetic Resonance (DE-CMR) imaging for atrial wall fibrosis detection was used in several studies to guide AF ablation. The aim of present study was to systematically review the literature on the role of atrial fibrosis detected by DE-CMR imaging on AF ablation outcome. Methods: Eight bibliographic electronic databases were searched to identify all published relevant studies until 21st of March, 2016. Search of the scientific literature was performed for studies describing DE-CMR imaging on atrial fibrosis in AF patients underwent Pulmonary Vein Isolation (PVI). Results: Of the 763 citations reviewed for eligibility, 5 articles (enrolling a total of 1040 patients) were included into the final analysis. The overall recurrence of AF ranged from 24.4 - 40.9% with median follow-up of 324 to 540 days after PVI. With less than 5-10% fibrosis in the atrial wall there was a maximum of 10% recurrence of AF after ablation. With more than 35% fibrosis in the atrial wall there was 86% recurrence of AF after ablation. Conclusion: Our analysis suggests that more extensive left atrial wall fibrosis prior ablation predicts the higher arrhythmia recurrence rate after PVI. The DE-CMR imaging modality seems to be a useful method for identifying the ideal candidate for catheter ablation. Our findings encourage wider usage of DE-CMR in distinct AF patients in a pre-ablation setting.

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Role of imaging in assessment of atrial fibrosis in patients with atrial fibrillation: state-of-the-art review

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jet116 ◽

2013 ◽

Vol 15 (1) ◽

pp. 1-5 ◽

Cited By ~ 42

Author(s):

L. Longobardo ◽

M. C. Todaro ◽

C. Zito ◽

M. C. Piccione ◽

G. Di Bella ◽

...

Keyword(s):

Atrial Fibrillation ◽

State Of The Art ◽

Atrial Fibrosis

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Increased α-Actinin-2 Expression in the Atrial Myocardium of Patients with Atrial Fibrillation Related to Rheumatic Heart Disease

Cardiology ◽

10.1159/000446362 ◽

2016 ◽

Vol 135 (3) ◽

pp. 151-159 ◽

Cited By ~ 3

Author(s):

Lei Zhang ◽

Nan Zhang ◽

Xuejiao Tang ◽

Fajin Liu ◽

Suxin Luo ◽

...

Keyword(s):

Atrial Fibrillation ◽

Heart Disease ◽

Sinus Rhythm ◽

Rheumatic Heart Disease ◽

Collagen Content ◽

Atrial Fibrosis ◽

Smad Pathway ◽

Smad Signaling Pathway ◽

Tgf Β1 ◽

Rheumatic Heart

Objectives: Atrial ﬁbrosis, a marker of atrial structural remodeling, plays a critical role in atrial ﬁbrillation (AF). α- Actinin-2 is associated with structural remodeling related to stretching. The transforming growth factor-β1 (TGF-β1)/Smad pathway plays an important role in atrial fibrosis. We investigated the effects of the TGF-β1/Smad signaling pathway on α-actinin-2 in atrial fibrosis in patients with AF. Methods: Forty-one right atrial specimens obtained from patients with rheumatic heart disease (RHD) were divided into a chronic (c)AF group, i.e. RHD + cAF (n = 29), and a sinus rhythm group, i.e. RHD + sinus rhythm (n = 12). Patients with congenital heart disease (CHD) and sinus rhythm who underwent heart surgery served as controls (n = 10). Fibrosis was assessed by histological examination, and expression of α-actinin-2, TGF-β1 and Smad2/phosphorylated Smad2 (p-Smad2) was evaluated by immunohistochemistry, quantitative real-time PCR and Western blotting. In rat atrial fibroblasts treated with TGF-β1, the collagen content was measured using hydroxyproline detection, and α-actinin-2 and p-Smad2 were evaluated by semiquantitative reverse-transcription PCR and Western blotting. Results: The histology results revealed a significant increase in atrial fibrosis in AF patients. The collagen content, mRNA and protein expression levels of α-actinin-2 and the components of the TGF-β1/Smad signaling pathway were significantly gradually increased in the CHD + sinus rhythm, RHD + sinus rhythm and RHD + cAF groups (p < 0.05). The mRNA and protein levels of α-actinin-2 and TGF-β1 in RHD patients were positively correlated with the collagen volume fraction. A positive correlation between the expression of α-actinin-2 and TGF-β1 was also observed. In rat atrial fibroblasts treated with TGF-β1, the collagen content was greater than that in the control group (p < 0.05), and the expression levels of α- actinin-2 and p-Smad2 were also upregulated (p < 0.05). Conclusions: α-Actinin-2 expression was increased in the atrial tissues of patients with AF secondary to RHD. α-Actinin-2 was upregulated via the TGF-β1/Smad pathway in atrial fibroblasts, which suggests that it may be involved in TGF-β1/Smad pathway-induced atrial fibrosis in patients with AF.

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A Review of the Molecular Mechanisms Underlying Cardiac Fibrosis and Atrial Fibrillation

Journal of Clinical Medicine ◽

10.3390/jcm10194430 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4430

Author(s):

Grażyna Sygitowicz ◽

Agata Maciejak-Jastrzębska ◽

Dariusz Sitkiewicz

Keyword(s):

Atrial Fibrillation ◽

Molecular Mechanisms ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Signalling Pathways ◽

Ang Ii ◽

Atrial Fibrosis ◽

Genes Encoding ◽

Tgf Β1

The cellular and molecular mechanism involved in the pathogenesis of atrial fibrosis are highly complex. We have reviewed the literature that covers the effectors, signal transduction and physiopathogenesis concerning extracellular matrix (ECM) dysregulation and atrial fibrosis in atrial fibrillation (AF). At the molecular level: angiotensin II, transforming growth factor-β1, inflammation, and oxidative stress are particularly important for ECM dysregulation and atrial fibrotic remodelling in AF. We conclude that the Ang-II-MAPK and TGF-β1-Smad signalling pathways play a major, central role in regulating atrial fibrotic remodelling in AF. The above signalling pathways induce the expression of genes encoding profibrotic molecules (MMP, CTGF, TGF-β1). An important mechanism is also the generation of reactive oxygen species. This pathway induced by the interaction of Ang II with the AT2R receptor and the activation of NADPH oxidase. Additionally, the interplay between cardiac MMPs and their endogenous tissue inhibitors of MMPs, is thought to be critical in atrial ECM metabolism and fibrosis. We also review recent evidence about the role of changes in the miRNAs expression in AF pathophysiology and their potential as therapeutic targets. Furthermore, keeping the balance between miRNA molecules exerting anti-/profibrotic effects is of key importance for the control of atrial fibrosis in AF.

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Maternal endotoxemia induces renal collagen deposition in adult offspring: Role of NADPH oxidase/TGF-β1/MMP-2 signaling pathway

Archives of Biochemistry and Biophysics ◽

10.1016/j.abb.2020.108306 ◽

2020 ◽

Vol 684 ◽

pp. 108306 ◽

Cited By ~ 2

Author(s):

Juliane S. Farias ◽

Kelly M. Santos ◽

Natália K.S. Lima ◽

Edjair V. Cabral ◽

Regina S. Aires ◽

...

Keyword(s):

Nadph Oxidase ◽

Signaling Pathway ◽

Adult Offspring ◽

Collagen Deposition ◽

Tgf Β1

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P6082The role of left atrial fibrosis progression detected by LGE-MRI on the post-ablation atrial fibrillation recurrence

European Heart Journal ◽

10.1093/eurheartj/ehy566.p6082 ◽

2018 ◽

Vol 39 (suppl_1) ◽

Author(s):

M Kheirkhahan ◽

D C Peritz ◽

M Goldooz ◽

A Baher ◽

A K Morris ◽

...

Keyword(s):

Atrial Fibrillation ◽

Left Atrial ◽

Atrial Fibrillation Recurrence ◽

Atrial Fibrosis ◽

Fibrosis Progression ◽

Left Atrial Fibrosis

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Galectin-3 Induces Atrial Fibrosis by Activating the TGF-β1/Smad Pathway in Patients with Atrial Fibrillation

Cardiology ◽

10.1159/000506072 ◽

2020 ◽

Vol 145 (7) ◽

pp. 446-455 ◽

Cited By ~ 1

Author(s):

Minghan Xiao ◽

Meixia Zhang ◽

Mengjun Bie ◽

Xiaowen Wang ◽

Jingwen Guo ◽

...

Keyword(s):

Atrial Fibrillation ◽

Heart Disease ◽

Sinus Rhythm ◽

Rheumatic Heart Disease ◽

Atrial Fibrosis ◽

Smad Pathway ◽

Galectin 3 ◽

The Relationship ◽

Tgf Β1 ◽

Rheumatic Heart

Background: Atrial fibrosis plays a critical role in the occurrence and maintenance of atrial fibrillation. The role of TGF-β1 in mediating atrial fibrosis is well documented. The β-galactoside-binding lectin galectin-3 (Gal-3) is mainly produced by macrophages in biological events such as inflammation and angiogenesis. Previous studies have shown that Gal-3 is associated with atrial fibrosis, but the relationship between TGF-β1 and Gal-3 in atrial fibrosis remains unclear. Objective: To determine whether Gal-3 induces atrial fibrosis and atrial fibrillation by activating the TGF-β1/Smad pathway and whether the expression of Gal-3 is mediated by TGF-β1, which can enable assessing the relationship between Gal-3 and TGF-β1 in atrial fibrosis. Methods: In this study, 30 patients’ right atrial appendages were collected and divided into 3 groups: congenital heart disease sinus rhythm group (n = 10, as a control group), rheumatic heart disease sinus rhythm group (n = 10), and rheumatic heart disease atrial fibrillation group (n = 10). Rat atrial fibroblasts were cultured in vitro, and recombinant Gal-3 and recombinant TGF-β1 proteins were added to the cell culture. The expression of Gal-3, TGF-β1, Smad2, and collagen I was detected by Western blotting and quantitative real-time PCR. Atrial tissues were stained with Masson’s trichrome stain to evaluate the extent of atrial fibrosis. The expression of Gal-3 and TGF-β1 was detected by immunohistochemical staining and immunofluorescence staining. Gal-3 and TGF-β1 interaction was demonstrated by immunoprecipitation. Results: The expression levels of Gal-3, TGF-β1, Smad2, and collagen I were elevated in the rheumatic heart disease atrial fibrillation group compared with the congenital heart disease sinus rhythm group and the rheumatic heart disease sinus rhythm group. In cultured atrial fibroblasts, there is a synergistic interaction between Gal-3 and TGF-β1. Gal-3 stimulated the TGF-β1/Smad pathway, and overexpression of TGF-β1 induced Gal-3 expression. Conclusions: Gal-3 and TGF-β1 interact with each other and stimulate the downstream TGF-β1/Smad pathway. This finding suggests that Gal-3 could be an important factor in TGF-β1-induced fibrosis in atrial fibrillation.

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