Kai Huang,* Jie Lu,* Qin Li, Chuyi Wang, Sufan Ding, Xiangyang Xu, Lin Han

Department of Cardiovascular Surgery, Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Lin Han, Email sh_hanlin@hotmail.com

Background: The accumulation of epicardial adipose tissue (EAT) is associated with cardiometabolic risks and adverse outcomes in heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF). This study aims to identify genes secreted by EAT that contribute to the shared pathogenesis of HFpEF and AF, potentially serving as biomarkers for diagnosis.
Methods: Data sets from the GEO database for HFpEF-EAT, HFpEF-heart tissue, AF-EAT, AF-PBMC, and AF-heart tissue were analyzed. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) identified key genes in EAT linked to HFpEF and AF. Functional enrichment and connectivity map analyses explored common pathways and therapeutic targets. Machine learning techniques, including LASSO regression, random forest, and support vector machine, identified shared biomarkers. CIBERSORT was used to assess immune cell infiltration, while gene set enrichment analysis identified pathways related to hub genes. Receiver operating characteristic (ROC) curve analysis and experimental validation assessed the bioinformatics findings.
Results: In the HFpEF dataset, 200 key genes were identified by intersecting HFpEF-EAT, HFpEF-heart tissue, WGCNA analyses, and secretory proteins. For AF, 232 related genes were identified through similar methods. Thirteen genes were common between HFpEF and AF, with two central genes, ITPKA and WNT9B, selected as potential biomarkers through machine learning and ROC analysis. Immune cell infiltration and gene set enrichment analysis revealed pathways related to ITPKA/WNT9B. These patterns were confirmed in human samples.
Conclusion: This study identified EAT-derived secretory proteins as potential biomarkers for HFpEF and AF, with ITPKA and WNT9B as central hub genes. These findings offer insights into potential diagnostic and therapeutic strategies for HFpEF and AF.

Keywords: heart failure with preserved ejection fraction, atrial fibrillation, epicardial adipose tissue, diagnostic value, secretory proteins