Key result
Empagliflozin preserves cardiac function and reduces myocardial fibrosis by suppressing CCL2 expression in fibroblasts.
Why the study?
The mechanisms underlying the cardioprotective effects of sodium–glucose cotransporter 2 inhibitors, particularly in the absence of diabetes, remain unclear.
Does empagliflozin improve cardiac function and reduce fibrosis in mouse models of heart failure induced by transverse aortic constriction?
Does empagliflozin improve cardiac function and reduce fibrosis in mouse models of heart failure induced by transverse aortic constriction?
Empagliflozin demonstrates a novel antifibrotic mechanism in heart failure by directly acting on mechanically stressed cardiac fibroblasts to reduce chemokine signaling and macrophage-mediated inflammation.
Hypothesis-generating in mouse HF models; clinical translation and practice change require human trials.
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.
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Nakai et al. (2026) studied this question. Empagliflozin preserved cardiac function, reduced myocardial fibrosis and HF markers, and lowered cardiac CCR2+ macrophages by suppressing CCL2 expression in fibroblasts.
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