Single-cell transcriptomics reveals Cdh2–Vegfa-mediated myocyte communication as a mechanism of empagliflozin in heart failure with preserved ejection fraction

Background and purpose: Heart failure with preserved ejection fraction (HFpEF) poses a significant clinical challenge due to limited therapeutic options. Recent clinical trials have highlighted the potential benefits of empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with HFpEF; however, the molecular mechanisms mediating these effects remain elusive. This study aimed to unravel the molecular mechanisms by which empagliflozin exerts its therapeutic effects in HFpEF. Methods: Using a classical mouse model of HFpEF, we applied single-nucleus ribonucleic acid-sequencing (snRNA-seq) to comprehensively assess the impact of empagliflozin administration and subsequent withdrawal on myocardial tissue single-cell populations. Differentially expressed genes across various biological pathways were identified, and bioinformatics analyses were performed to uncover cellular interactions and signaling cascades modulated by empagliflozin. Results: Empagliflozin treatment significantly altered the expression of genes related to cardiac muscle contraction, neurodegeneration, fluid shear stress and atherosclerosis, and oxidative phosphorylation. Correlation analysis suggested that empagliflozin promoted communication between myocytes (MCs) and both Schwann cells (SCs) and endothelial cells (ECs) via cadherin-2 (Cdh2) and vascular endothelial growth factor A (Vegfa), contributing to improved cardiac function in HFpEF. Western blot confirmed that empagliflozin reversed the downregulation of Cdh2, Vegfa, and vascular endothelial growth factor receptor 2 (Vegfr2). Conclusions: SCs are implicated in HFpEF pathophysiology, and Cdh2 and Vegfa are identified as potential targets through which empagliflozin enhances MC, SC and MC, EC communication to improve cardiac function. These findings provide new insights into the pathogenesis of HFpEF and the mechanisms underlying empagliflozin therapy.