Abstract 4142984: Sex Differences in Atrial Fibrillation: Insights from Metabolomics and Transcriptomics

Background: Patients with atrial fibrillation (AF) show different prevalence, complications and prognosis between sexes, which increases the difficulties of risk stratification and therapy strategy management. However, the underlying reasons remain unclear. Hypothesis: Plasma metabolites might contribute to sex differences in AF. Methods: Plasma samples of male and female patients with AF were collected and performed with metabolomics analysis. Transcriptomics data of atrial tissue from GEO database was analyzed based on a sex stratification. Metabolomics and transcriptomics data were further integratedly analyzed to explore the association among metabolites, atrial remodeling and AF. The related different expressed genes were validated by qPCR. Results: Metabolomics analysis showed 155 higher-level metabolites and 408 lower-level metabolites in female patients with AF compared to male patients. And a total of 41 annotated metabolites were further identified. Especially, plasma level of phenylalanine was significantly lower in female patients with AF compared with male patients (FC 0.79, p <0.05) while plasma levels of phenylalanine derived-metabolites, including 3,4-dihydroxyphenylacetic acid and 4-hydroxybenzoic acid were significantly higher in female patients with AF compared with male patients (FC 1.71, p <0.05; FC 2.29, p <0.05). KEGG pathway analysis also showed differential metabolites were enriched in phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism pathways. Transcriptomics analysis of left atrium suggested that atrial remodeling in males with AF was prone to be enriched in metabolic pathways while that in females was strongly enriched in inflammation related pathways. Moreover, related genes responded to phenylalanine and phenylalanine derived-metabolites such as NRF2, GPX4 were both significantly unregulated in left atrium of AF patients compared to those of sinus rhythm (SR) patients in males (FC 3.96, p <0.01; FC 2.20, p <0.05) while were not significantly altered between AF and SR patients in females (both p >0.05). Conclusion: This study highlights sex differences of plasma metabolites in patients with AF and their association with differential transcriptomic signature of left atrium. The findings provide new insights into understanding sex differences in AF and identify several specific metabolites, which underscores the importance of taking sex differences into consideration during decision making in clinical practice.