Gender differences in fibrosis remodeling in patients with long-standing persistent atrial fibrillation.

Zhi Li,Zengwei Wang,Jinsong Han,Zongtao Yin,Yan Zhu,Maximilian Y Emmert,Jian Zhang,Xiaodong Xue,Huishan Wang,Yuji Zhang

doi:10.18632/oncotarget.16342

Abstract

The success rate of catheter ablation in atrial fibrillation (AF) is known to be lower in females than in males. However, while the exact mechanism for this phenomenon remains to be elucidated, tissue fibrosis may play an important role in this regard. It has been shown that fibrosis promotes AF and its recurrence, thereby substantially reducing the efficacy of catheter ablation in AF patients. Thus, we hypothesized that fibrosis may contribute to gender differences in the outcomes of AF catheter ablation.Here we systematically assessed pulmonary vein sleeves obtained from 166 patients with and without long-standing persistent-AF (LSP-AF) in order to identify gender-specific mechanistic differences in fibrosis remodeling of AF patients.Histological analysis revealed that the female LSP-AF group, rather than its male counterpart, had a higher degree of fibrosis when compared to the NON-AF group. Further analysis using microarray, immunohistochemistry and Western Blot displayed that gender differences in fibrosis remodeling of LSP-AF were mainly due to the inherent differential expression of fibrosis-related genes (n=32) and proteins (n=6). Especially, those related to the TGFβ/Smad3 pathway appeared to be up-regulated in the female LSP-AF group thus promoting an aggravation of fibrosis remodeling. In summary, our data suggest that the aggravation of fibrosis remodeling in women may be an important reason for the low success rate of AF catheter ablation when compared to men. Therefore, inhibiting the TGFβ/Smad3 pathway-mediated fibrosis could represent an interesting target for future therapeutic concepts to improve the success rate of AF catheter ablation in women.

Highlights

Atrial fibrillation (AF) is one of the most prevalent arrhythmias worldwide and it is related to an increased cardiovascular morbidity and mortality [1]
The results revealed statistical significance in females with an optimal cut-off value for female Collagen volume fraction (CVF) to predict the presence of long-standing persistent-AF (LSP-AF) of was > 16.72%, with 56.7% specificity and 83.6% sensitivity (AUC = 0.7, 95% CI: 0.591-0.795, P < 0.01), while there was no statistical significance in male CVF to predict the presence of LSP-AF (AUC = 0.508, 95% CI: 0.395-0.621, P = 0.902)
Further analysis demonstrated that these gender differences in fibrosis remodeling of LSP-AF were mainly due to inherent differential expression of fibrosisrelated genes and proteins

Summary

Introduction

Atrial fibrillation (AF) is one of the most prevalent arrhythmias worldwide and it is related to an increased cardiovascular morbidity and mortality [1]. Gender-specific differences in AF patients are widely neglected, and substantial knowledge gaps do exist in the understanding of epidemiology, pathophysiology, presentation, and prognosis between men and women [2]. Recent studies have suggested that the incidence, clinical presentation and consequences of AF are different between genders. With regards to the treatment of AF patients, catheter-ablation represents a reasonable therapy strategy for both genders. Women are more likely to experience higher frequency of recurrence when compared to men [5]. Fibrosis www.impactjournals.com/oncotarget remodeling leads to a dissociation in atrial conduction and thereby promotes AF which results in a lower efficacy of ablation therapy. It has been suggested that the more extensive the fibrosis is, the more ineffective the ablation therapy becomes [7]

Methods

Results

Conclusion