Follicle-stimulating hormone promotes atrial fibrosis in menopausal women with atrial fibrillation

Abstract

BackgroundPostmenopausal women with atrial fibrillation (AF) exhibit a higher level of atrial fibrosis and a higher recurrence rate after ablation compared with men. However, the underlying mechanism remains unclear. ObjectiveThe purpost of this study was to investigate the mechanism through which menopause promotes atrial fibrosis. MethodsIn a prospective cohort of women with AF, regression analyses were conducted to assess the relationship between low-voltage area (LVA) and sex hormone levels. CREM-IbΔC-X mice, a spontaneous AF model, underwent bilateral ovariectomy (OVX). Electrocardiograms, echocardiograms, and Masson staining were performed. Follicle-stimulating hormone (FSH) stimulation was applied in male mice for 3 months. OVX was also applied in an angiotensin II (Ang II)–induced pressure overload mouse model, after programmed electrical stimulation and structural analyses. Bulk RNA sequencing (RNA-seq) was performed to elucidate potential mechanisms. ResultsWomen demonstrated a significantly higher LVA burden than men (P < .001). A positive correlation was observed between LVA burden and FSH level (P = .002). Mice in the OVX group exhibited a significantly higher incidence of AF (P = .040) and atrial fibrosis (P = .021) compared with the Sham group, which could be attenuated by adeno-associated virus encoding small interfering RNA against Fshr. In male CREM-IbΔC-X mice, FSH stimulation promoted the occurrence of AF (P = .035) and atrial fibrosis (P = .002). In Ang II–induced female mice, OVX prompted atrial fibrosis, increased AF inducibility, and shortened atrial effective refractory period, which could be attenuated with knockdown of Fshr. RNA-seq indicated mitochondrial dysfunction. ConclusionPostmenopausal women exhibited a higher LVA burden than men, which was positively correlated with FSH level. FSH promoted atrial fibrosis through oxidative stress.