SGLT2i attenuates biventricular remodeling and preserves connexin 43 in experimental volume-overload heart failure

Abstract

Abstract Heart failure (HF) caused by chronic volume overload is associated with progressive structural, electrical, and metabolic remodeling, leading to ventricular dysfunction and increased arrhythmogenic risk. Although sodium–glucose cotransporter-2 inhibitors (SGLT2i) provide significant cardioprotection, their glucose-independent mechanisms remain incompletely understood. This study examined the effects of the SGLT2i empagliflozin on biventricular myocardial remodeling in a rat model of volume-overload HF induced by aortocaval fistula (ACF), with emphasis on extracellular matrix (ECM) remodeling and gap-junctional communication. Volume overload resulted in pronounced cardiac hypertrophy, ventricular dilation, fibrosis, oxidative stress, and cellular injury, accompanied by reduced and mislocalized connexin 43 (Cx43) and increased connexin 45 (Cx45) expression. These changes were associated with elevated pro-fibrotic and stress markers (GDF15, Galectin-3, FGF21) and altered protein kinase C (PKC) signaling. SGLT2i treatment significantly attenuated hypertrophy, reduced collagen deposition, oxidative stress, and tissue damage, and partially improved systolic function. Importantly, SGLT2i preserved Cx43 expression and Ser368 phosphorylation, prevented maladaptive Cx45 upregulation, and improved ECM remodeling. Modulation of PKCε and PKCδ suggests activation of protective intracellular pathways. In conclusion, SGLT2i exerts multifaceted cardioprotective effects in volume-overload HF independent of glycemic control, improving structural and electrical myocardial integrity and potentially reducing arrhythmogenic risk.