Glucose-independent effects of empagliflozin on gap junction and extracellular matrix remodeling in volume overload heart failure
M Sykora, K Ondrejak Andelova, T Egan Benova, N Andelova, E Goncalvesova, N Tribulova, B Szeiffova BacovaAbstract
Background
Heart failure (HF) caused by chronic volume overload is characterized by progressive ventricular dilation, myocardial fibrosis, and electrical remodeling, which together contribute to systolic dysfunction and increased arrhythmogenic risk. Disruption of gap junctional communication, particularly involving connexin-43 (Cx43), and maladaptive extracellular matrix (ECM) remodeling are key mechanisms underlying disease progression. Sodium–glucose cotransporter-2 inhibitors (SGLT2i) improve clinical outcomes in HF independent of glycemic control; however, the myocardial mechanisms linking SGLT2i therapy to structural and electrical stabilization remain incompletely understood.
Purpose
To investigate glucose-independent effects of empagliflozin on myocardial structural and electrical remodeling in experimental volume overload HF, with emphasis on gap junction integrity, ECM remodeling, and intracellular signaling pathways relevant to HF progression.
Methods
Heart failure was induced in male Wistar rats by aortocaval fistula (ACF). After HF development, animals were treated with empagliflozin (10 mg/kg/day) for four weeks. Cardiac structure and function were assessed by transthoracic echocardiography. Myocardial fibrosis, oxidative stress, and tissue injury were evaluated using histological and biochemical methods. Expression, phosphorylation, and distribution of connexins (Cx43, Cx45), ECM remodeling markers (MMP-2, FGF21, GDF15, galectin-3), and protein kinase C (PKC) isoforms were analyzed in both left and right ventricles.
Results
Volume overload HF resulted in marked ventricular hypertrophy and dilation, impaired systolic function, increased myocardial fibrosis, oxidative stress, and cellular injury. These changes were accompanied by reduced total and phosphorylated Cx43, increased Cx45 expression, and activation of profibrotic and stress-related markers, indicating formation of a proarrhythmogenic myocardial substrate. Empagliflozin significantly attenuated cardiac hypertrophy, reduced collagen deposition, oxidative stress, and tissue damage, and partially improved systolic performance. Importantly, empagliflozin preserved myocardial Cx43 expression and Ser368 phosphorylation, prevented maladaptive upregulation of Cx45, and improved gap junction integrity. These effects were associated with modulation of PKC signaling, suggesting activation of cardioprotective intracellular pathways.
Conclusion
Empagliflozin exerts multifaceted cardioprotective effects in volume overload–induced HF independent of glucose lowering. By simultaneously modulating ECM remodeling and preserving gap junctional communication, empagliflozin may reduce arrhythmogenic substrate formation and promote favorable ventricular remodeling, providing mechanistic support for the clinical benefits of SGLT2 inhibition in HF.