Cardioprotection of Empagliflozin in Rodent Volume Overload Heart Failure: Structural and Electrical Benefits

Objective: Heart failure (HF) caused by chronic volume overload is characterized by adverse myocardial structural, electrical, and metabolic remodelling, resulting to impaired cardiac function and increased arrhythmogenic risk. Sodium–glucose cotransporter-2 inhibitors (SGLT2i) exert robust clinical benefits in HF; however, the glucose-independent cardioprotective mechanisms are incompletely understood. We aimed to investigate/elucidate the effects of the SGLT2 inhibitor empagliflozin on myocardial remodelling in volume overload–induced HF in rats focusing on extracellular matrix (ECM) alterations, intercellular gap-junctions integrity, and modulation of intracellular signalling pathways. Design and method: HF was induced in male Wistar rats by aortocaval fistula and four weeks later, empagliflozin (10 mg/kg/day) was administered for next four weeks. Cardiac function was assessed by echocardiography. Heart, left and right ventricular weight was monitored, and myocardial structural remodelling was examined using histology, biochemical assays, immunofluorescence, and Western blotting of connexins, extracellular markers and protein kinase C (PKC) isoforms. Results: Volume overload resulted in marked cardiac hypertrophy and ventricular dilation along with fibrosis, oxidative stress, and cellular injury, accompanied by reduced and mislocalized connexin 43 (Cx43), increased connexin 45 (Cx45), and activation of pro-fibrotic markers (GDF15, galectin-3, FGF21). Empagliflozin significantly attenuated hypertrophy, reduced collagen deposition and oxidative stress, and partially improved systolic function. Importantly, SGLT2i preserved myocardial Cx43 expression and its Ser368 phosphorylation, prevented maladaptive Cx45 upregulation, and improved structural remodelling. These effects were associated with modulation of PKC signalling, particularly increased PKC∊ and reduced PKCδ activity, suggesting activation of cardioprotective intracellular pathways. Conclusions: Empagliflozin exerts multifaceted cardioprotective effects in volume overload–induced heart failure independent of its glycaemic action. By improving myocardial structural integrity and suppressing profibrotic as well as stress-related signalling and particularly by upregulation of Cx43 mediated electrical coupling Empagliflozin may reduce arrhythmogenic risk as well as slows down heart failure. This study was supported by Slovak Research and Development Agency (under the contract no. VV-MVP-24-0278, no. 21–0410 and no. 22–0264), Scientific Grant Agency of the Ministry of Education, Research, Development and Youth of the Slovak Republic and Slovak Academy of Sciences (under the contracts no. 2/0006/23 and no. 2/0133/24).