Effect of sotagliflozin on ventricular arrhythmias in mice with myocardial infraction

Background: Ventricular arrhythmias (VAs) after myocardial infarction (MI) are an important cause of death in patients. Inhibition of sodium-glucose ligand transporter type 2 (SGLT-2) has been shown to reduce cardiovas-cular mortality in myocardial infarction independent of glycemic sham and prevent ventricular arrhythmias, and it is unclear whether these effects can be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1 and 2 inhibitor sotagliflozin (Sto) on VAs and their underlying mechanisms after MI.Methods: MI was induced by ligation of the left anterior coronary artery in 6-8 weeks-old male mice, which were fed Sto at a dose of 30 mg/kg/day for 4 weeks after surgery. The effects were assessed by echocardiography, histopathology, Langendorff Heart Perfusion System, ambulatory electrocardiography, and Western blot. In vitro experiments were performed to assess the effect of Sto on cardiomyocytes subjected to hypoxic.Results: Compared to the MI group, Sto treatment significantly improved cardiac function and reduced infarct size and fibrosis levels. Sto also decreased action potential duration (APD) and APD alternation thresholds. Ambulatory ECG and BURST stimulation showed that Sto reduced the incidence of VAs. In addition, Sto significantly improved the expression levels of ion channels and CX43 and ameliorated the abnormal expression of Ca2+ handling proteins after MI. Mechanistically, in vivo and in vitro experiments confirmed that TLR4/ CaMKII activation was enhanced after MI, while Sto significantly inhibited the activation of the TLR4/CaMKII signaling pathway.Conclusion: Sto improved LV remodeling and reduced the incidence of VAs after MI, which was regulated by modulating the TLR4/CaMKII signaling pathway.

Automated summary

Chronic treatment with the dual SGLT-1 and 2 inhibitor sotagliflozin (Sto) improves left ventricular remodeling and reduces the incidence of ventricular arrhythmias (VAs) after myocardial infarction (MI) by modulating the TLR4/CaMKII signaling pathway.