Empagliflozin Restores Cardiac Metabolism and Suppresses Immune Activation in Acute Myocardial Infarction
Description
Background and aims: Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, 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 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 hours 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 ketone body levels in mice with AMI. Additionally, it suppressed accumulation of UDP-glucose and GM3 gangliosides. Notably, the effect of EMPA on cardiac metabolome and lipidome was independent of hyperglycemia. Furthermore, EMPA reduced leukocytes 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 diabetes. These metabolic effects correlate with lower immune cell infiltration and cardiac necrosis, providing long-term benefits in AMI. Keywords: Empagliflozin, type 2 diabetes, acute myocardial infarction, metabolomics, lipidomics, inflammation.