Rethinking left atrial remodelling across sexes: should we see beyond the size?

This editorial refers to ‘Sex-specific differences in left atrial reverse remodelling after successful catheter ablation for atrial fibrillation’, by Y. Yoshida et al., https://doi.org/10.1093/ehjci/jeaf309. Over the past two decades, catheter ablation has become a safe, and effective treatment for atrial fibrillation (AF), leading to reductions in AF burden and stroke, as well as improvements in symptoms and quality of life. Current guidelines recommend catheter ablation as a first-line approach for rhythm control.1 Despite these recommendations and a comparable lifetime risk of developing AF between women and men, women are poorly represented in randomized clinical trials evaluating the efficacy of AF therapies and are less referred for AF ablation.2,3 Additionally, female patients experience post-procedural lower arrhythmia-free survival with higher rate of procedural complications and stroke.2 These clinical disparities emphasize the importance of understanding the mechanisms underlying sex-related differences in post-procedural left atrial (LA) remodelling. In the current issue of the Journal, Yoshida et al. address this important question analysing sex-specific differences in LA reverse remodelling following successful AF catheter ablation in a cohort of 153 patients.4 Using echocardiographic LA strain analysis, it is demonstrated that while both sexes exhibited significant post-procedural improvements in LA structure and function, women exhibited a lesser increase in LA reservoir strain and higher degree of residual stiffness compared with men. Interestingly, female sex remained independently associated with reduced LA reverse remodelling and higher post-procedural brain natriuretic peptide levels, suggesting a less favourable remodelling response despite comparable baseline clinical and echocardiographic characteristics. The study by Yoshida et al. is methodologically robust, with a well-defined cohort and a comprehensive echocardiographic assessment. However, as a mechanistic study, it does not explore clinical outcomes within the analysed cohort. Moreover, in line with prior literature, women remain underrepresented (29.4% of the cohort), potentially reducing the statistical power to fully outline differences in LA remodelling patterns. Despite these limitations, these findings highlight potential biological and clinical determinants of sex disparities in AF characteristics and ablation outcomes and invite a broader reflection on how atrial remodelling is defined, characterized, and interpreted across sexes. Although this study reported no significant sex difference in baseline LA volume, this finding may reflect a more advanced stage of atrial remodelling in women as compared to their counterparts. Emerging evidence showed that the differences in LA cardiomyopathy between the two sexes are independent of the LA size.5,6 Electro-anatomical mapping studies have reported a higher prevalence and density of low-voltage areas in women, independently of age and LA size.5,7 Reduced atrial voltage has been associated with structural myocardial degeneration, characterized by interstitial fibrosis and myocyte vacuolar changes, as demonstrated in LA tissue specimen collected during the AF ablation procedures.8 Furthermore, cardiac magnetic resonance (CMR) studies have shown spatial concordance between low voltage regions and areas of delayed gadolinium enhancement, reinforcing the hypothesis that these electrical abnormalities might be a marker of underlying fibrosis.9,10 All these findings support the hypothesis that AF development in women may be related to the presence of advanced LA cardiomyopathy, whereas in men AF development might be driven by electrical remodelling and LA dilatation.5 This change of paradigm might be consistent with the epidemiological data demonstrating a higher incidence of AF in men as compared to women,1 while histological and electroanatomic studies show that women display a more severe LA myocardial degeneration.9 These sex-related differences in AF pathophysiology may also explain the less favourable LA remodelling reported by Yoshida et al, the poorer ablation outcome in women and their higher susceptibility to ischaemic stroke.2 Beyond structural and electrical factors, several gender-specific pathways may also contribute to those different remodelling patterns. Hormonal influence over cardiac ion channel regulation has been described.11 Moreover, differences pericardial fat metabolic activity have been associated with AF and atrial fibrosis in women, particularly after menopause.12 Another possible mechanism might be chronic inflammation, with women displaying a higher circulating C-reactive protein levels when compared to man.13 A deeper understanding of these mechanisms might facilitate a more precise definition of atrial disease staging and lead to a more tailored rhythm control strategy in both sexes. It is becoming evident that LA size and function do not have the same meaning across sexes and that current stratification methods—relying mainly on indexed LA volume evaluated with two-dimensional echocardiography—may underestimate the prevalence of LA cardiomyopathy in women.5,9 A more accurate characterization of LA disease will probably require a multimodal imaging approach. This might involve the identification of an optimal cut-off for LA volume and strain evaluated with two- and three-dimensional echocardiography, complemented by CMR quantification of LA fibrosis and epicardial fat,10,12 biomarker profiling,13 and artificial intelligence-based ECG phenotyping.14 Future studies should aim at validating these parameters to help improve risk stratification and allow earlier intervention in female patients with evolving atrial disease. In this context, the study by Yoshida et al provides valuable mechanistic insight and offers robust bases for future research to improve tailored AF management. Martina De Raffele (Conceptualization [equal]; Methodology [equal]; Writing—original draft [lead]; Writing—review & editing [equal]) and Victoria Delgado (MD PhD (Conceptualization [equal]; Methodology [equal]; Supervision [equal]; Writing—review & editing [equal])) Victoria Delgado received speaker fees from Abbott Structural, Edwards Lifesciences, GE Healthcare, JenaValve, Medtronic, Philips, Products&Features and Siemens and institutional research contracts with Philips. Martina De Raffele has nothing to disclose. Not applicable for this type of article.