Sotagliflozin corrects myocardial phenotype, mitochondrial gene expression and oxidative stress in mice with hypertrophic cardiomyopathy

Background Hypertrophic cardiomyopathy (HCM) is associated with mitochondrial dysfunction and oxidative stress. Objective Our goal was to determine the effects of the dual Sodium-Glucose-Linked-Transporter (SGLT) 1 and 2 inhibitor sotagliflozin (SOTA) on myocardial remodeling, diastolic function, mitochondrial gene expression and oxidative stress in mice with HCM due to the tropomyosin E180G mutation (E180G). Methods E180G and non-carrier (NC) mice 7–8 weeks old were randomized to SOTA formulated in the chow (30 mg/kg chow) or control diet (CD) for 8 weeks. Cardiac structure and function were assessed by echocardiography at baseline, and after 4 and 8 weeks of treatment. At 8 weeks mice were sacrificed to assess myocardial histology, RNA expression and oxidative stress. Results At baseline E180G mice had myocardial hypertrophy and diastolic dysfunction that worsened over the next 8 weeks. In E180G mice, treatment with SOTA for 8 weeks prevented further LV hypertrophy, decreased interstitial fibrosis, normalized diastolic function and decreased atrial size. In E180G hearts mitochondrial gene sets were downregulated and oxidative stress was increased. SOTA treatment upregulated mitochondrial gene sets and prevented the increase in oxidative stress. Upregulated fibrosis gene sets in E180G hearts were not affected by SOTA. Conclusions In a mouse model of HCM, SOTA exerts beneficial effects on myocardial structure and diastolic function which are associated with restoration of down-regulated mitochondrial gene programs and correction of oxidative stress. SOTA may be of clinical value in the treatment of patients with HCM.