Abstract
BACKGROUND AND AIMS: Empagliflozin (EMPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), is cardioprotective in acute myocardial infarction (AMI) including fewer hospitalizations for heart failure. However, the underlying metabolic and immunomodulatory mechanisms remain incompletely characterized. This study investigates the metabolic effects of EMPA in diabetic and non-diabetic conditions, as well as on AMI-induced immune responses. METHODS: C57BL/6J mice were fed on either a control Chow diet (CD) or Western diet (WD) to induce hyperglycemia, followed by treatment with EMPA (10 mg/kg/day) for six weeks and subsequent AMI (30 min of ischemia/2 h of reperfusion). Infarcted hearts were subjected to metabolomic and lipidomic analyses. Cardiac necrosis and immune cell abundance were assessed 7 days post-AMI in blood, spleen, and cardiac tissue with Hematoxylin/Eosin (H/E) staining and flow cytometry, respectively. RESULTS: Besides the already established effects of EMPA in lowering body weight, blood glucose and cholesterol levels, we found that it fully restored cardiac ATP and 3-hydroxybutyrate (3-BHB) levels in mice with AMI. Additionally, it suppressed UDP-glucose and GM3 ganglioside levels. Notably, the ability of EMPA to restore cardiac metabolome and lipidome was similar between the two dietary groups, with a more pronounced effect observed in WD-fed mice. Furthermore, EMPA reduced myeloid cells in spleen (15.42 ± 2.60 % vs. 21.20 ± 4.45 %) and cardiac tissue (15.94 ± 5.93 % vs. 32.42 ± 8.77 %) and suppressed cardiac necrosis 7 days post-AMI (11.15 ± 3.42 % vs. 21.74 ± 3.30 %). CONCLUSIONS: EMPA restores cardiac energetics and attenuates the metabolic complications of AMI, independent of the presence of diabetes. These metabolic effects correlate with lower immune cell infiltration and cardiac necrosis, providing long-term benefits in AMI.