Early empagliflozin administration in mice after ischemic injury improved ejection fraction and cardiac output at 30 days, reduced myocardial fibrosis, and attenuated inflammatory monocyte expansion.
RCT (n=21)
randomized
Does empagliflozin improve cardiac function and modulate immune cell dynamics in a mouse model of ischemic heart failure?
Early empagliflozin administration after ischemic injury in mice improves cardiac function and limits fibrosis, potentially mediated by modulation of inflammatory monocyte dynamics.
Abstract Introduction Acute myocardial infarction (AMI) and ischemic heart failure (HF) remain major causes of mortality and morbidity worldwide. Empagliflozin (EMPA), a selective SGLT2 inhibitor, is approved for HF treatment across the full spectrum of left ventricular ejection fraction, independent of type 2 diabetes. Although immune cells are recognized contributors to HF progression, the effects of EMPA on immune cell dynamics in ischemic HF remain insufficiently understood. Aim We aimed to 1) evaluate the impact of early EMPA treatment after ischemic injury on cardiac function and fibrosis, 2) to characterize immune cell populations in the blood, bone marrow (BM), spleen, and heart, and 3) to explore the underlying mechanisms in BM, circulation, and the failing myocardium that may explain EMPA’s beneficial effects. Methods Twenty-one adult male C57BL/6J mice were randomized into three groups: Sham (n=5), HF control (n=8), and HF treated with EMPA (n=8). All mice underwent 30 minutes of myocardial ischemia followed by 30 days of reperfusion. EMPA (10 mg/kg/day) or vehicle was administered starting 1 hour post-reperfusion and continued daily. Echocardiography was performed at baseline, 48 hours, and 30 days post-AMI. At day 30, PBMCs and BM cells were isolated for proteomic analysis. Peripheral blood, BM, spleen, and heart tissues were analyzed by flow cytometry to assess immune populations. Hearts were collected for histology and molecular analyses. Results EMPA improved ejection fraction and cardiac output at 30 days, but not at 48 hours, compared with controls, and significantly reduced myocardial fibrosis. PBMC proteomics showed minor differences, whereas BM proteomics revealed substantial EMPA-induced changes involving NLRP3 inflammasome regulation, pentose phosphate pathway, glutathione synthesis, and innate immune pathways. In peripheral blood, HF increased CD11b+ cells and neutrophils, with no significant difference between HF control and EMPA-treated groups. EMPA reduced circulating T cells, including CD4+ and CD8+ subsets. In the BM, the HF-induced expansion of inflammatory Ly6Chigh monocytes was significantly attenuated by EMPA. No significant alterations in splenic immune populations were detected. In the myocardium, EMPA decreased Ly6Chigh monocyte infiltration, reduced CaMKII phosphorylation, and lowered MMP-2 levels compared to HF controls. EMPA did not affect STAT3 phosphorylation, IL-6 and ICAM-1 levels, or NF-κB activation. Conclusions Early EMPA administration after ischemic injury improves cardiac function and limits fibrosis, accompanied by modulation of inflammatory monocyte dynamics in the BM and myocardium. These immunomodulatory effects of empagliflozin merit further investigation.
Choustoulaki et al. (Fri,) conducted a rct in Ischemic heart failure (n=21). Empagliflozin vs. Vehicle (HF control) and Sham was evaluated on Cardiac function (ejection fraction and cardiac output) and myocardial fibrosis at 30 days. Early empagliflozin administration in mice after ischemic injury improved ejection fraction and cardiac output at 30 days, reduced myocardial fibrosis, and attenuated inflammatory monocyte expansion.