Empagliflozin Attenuates Cardiac Fibrosis by Suppressing Fibroblast‐Mediated C‐C Motif Chemokine Ligand 2 Expression

BACKGROUND: Despite recent advances in pharmacotherapy, heart failure (HF) remains a major cause of hospitalization and death, particularly among aging populations. Sodium-glucose cotransporter 2 inhibitors have reduced hospitalization for HF and cardiovascular death. However, the mechanisms underlying these cardioprotective effects, particularly in the absence of diabetes, remain unclear. Therefore, we aimed to define the cardiac-specific effects of sodium-glucose cotransporter 2 inhibitors and the mechanism by which they improve HF prognoses. METHODS: We investigated the cardioprotective properties of empagliflozin in mouse models of HF induced by transverse aortic constriction. Empagliflozin was administered daily for 2 weeks, starting 2 weeks after transverse aortic constriction, and then cardiac function was evaluated. RESULTS: Empagliflozin preserved cardiac function and markedly reduced myocardial fibrosis and HF markers. Empagliflozin decreased cardiac C-C chemokine receptor type 2-positive macrophages, suggesting attenuated inflammation. Empagliflozin also reduced C-C motif chemokine ligand 2 expression in cardiac fibroblasts, indicating direct modulation of fibroblast behavior under mechanical stress and inhibited recruitment of proinflammatory macrophages. CONCLUSIONS: We propose a novel antifibrotic mechanism in which empagliflozin acts directly on mechanically stressed cardiac fibroblasts to reduce chemokine signaling and macrophage-mediated inflammation. This mechanosensitive, fibroblast-targeted action might represent a paradigm shift in understanding sodium-glucose cotransporter 2 inhibitor cardioprotection and lead to new therapeutic strategies to mitigate HF progression.