Abnormal “Escherichia Shigella-EAT-LAAD” axis in HFrEF patients with AF and the regulatory effect of SGLT2 inhibitors

Background The role of epicardial adipose tissue (EAT) and gut microbiota (GM) in heart failure (HF) and atrial fibrillation (AF) have been extensively researched, but the role of them in individuals with concurrent HF with reduced ejection fraction (HFrEF) and AF (HFrEF_AF) is still unclear. Furthermore, the role of SGLT2i in HFrEF_AF patients is also not fully understood. The purpose of this study is to compare the differences in EAT and GM between HFrEF_AF and HFrEF patients without AF (HFrEF_NAF), and to analyse the relationship between them and the patients' heart structure, as well as the changes of them after SGLT2i treatment. Methods 45 HFrEF_NAF patients and 39 HFrEF_AF patients were continuously recruited, with 26 patients from each group meeting the selection criteria. Fecal samples and CT scans were collected at baseline and after SGLT2i treatment for 3 months, respectively. The 16S rRNA gene of fecal samples was sequenced, and EAT volume (EATV) and EAT volume index (EATVI) values were measured and calculated with CT. These patients were followed up for up to 12 months to assess their long-term re-hospitalization rates. Results The results showed that EATV [191.75 (119.59, 222.44) vs. 141.99 (97.10, 183.75)] and EATVI [105.07 (82.90, 116.39) mL/m 2 vs. 81.03 (55.12, 108.74) mL/m 2 ] in HFrEF_AF patients were significantly higher than in HFrEF_NAF patients. After adjusting for Age, Gender, CHD and BMI, Spearman correlation analysis showed that EATVI was significantly negatively correlated with post-conversion abundance of Escherichia coli ( R = −0.496, P = 0.019) and Escherichia Shigella ( R = −0.472, P = 0.027) in HFrEF_AF patients. The mediation analysis showed that Escherichia Shigella in HFrEF_AF patients had a significant indirect effect on LAAD through EATVI (ACME = −0.553, P = 0.042), but the direct and total effects were not significant. After 3 months of SGLT2i treatment, the connection between Escherichia Shigella , EATVI and LAAD disappeared in HFrEF_AF patients. Moreover, after SGLT2i treatment, harmful AF-related bacteria such as Catenibacterium are no longer enriched in HFrEF_AF patients, whereas beneficial bacteria such as Blautia are enriched. The 12 months follow-up showed no significant difference in re-hospitalization rate between HFrEF_NAF and HFrEF_AF patients. Conclusion EATV and EATVI in HFrEF_AF patients were significantly higher than in HFrEF_NAF patients. There may be an abnormal “ Escherichia Shigella -EAT-LAAD” axis in HFrEF_AF patients, and SGLT2i may benefit HFrEF_AF patients differently than HFrEF_NAF patients by inhibiting this axis. Clinical Trial Registration https://www.chictr.org.cn/showproj.html?proj=240632 , ChiCTR2400088128.