SGLT2 Inhibition and Exercise for the Diabetic Right Ventricle

Diabetes mellitus (DM) is a leading cause of death in the world, and significant risk factor for cardiovascular disease (CVD). Though DM is characterized by elevated blood glucose, significant diabetes-related morbidity and mortality is due to cardiovascular diseases. To date, the majority of diabetic cardiomyopathy research has been conducted in the left ventricle. However, in most disease contexts, right ventricular (RV) function predicts survival, yet little is known about the diabetic RV nor are there specific RV-targeted therapies. Sodium glucose co-transporter-2 inhibitors (SGLT2i) and exercise have clear cardioprotective effects, yet whether these interventions protect the RV in the setting of diabetes is unknown. To determine whether SGLT2i and exercise protect the diabetic RV, diabetic Sprague Dawley rats induced by streptozotocin (30 mg/kg) and a high-fat diet underwent a 13-week intervention of the SGLT2i canagliflozin (3mg/kg/day in 0.5% methylcellulose) with and without access to exercise. Indicators of diabetic cardiomyopathy were assessed by myocyte cell size, fibrosis by trichrome staining and expression of fibrotic mediators, and expression of molecular signature genes in failing heart (fetal gene program). Expression of pro-fibrotic mediators (collagen and α-SMA) were significantly attenuated with SGLT2i and exercise compared to sedentary controls. RV histology demonstrated significant evidence of diabetes-induced hypertrophy, and fibrosis that was attenuated in SGLT2i and exercise groups compared to sedentary controls and exercise and SGLT2i monotherapies. Together, we demonstrate that SGLT2i and exercise have protective effects on the RV in diabetic rats. The clinical implication of this data suggests a potential for therapeutic interventions that target the RV in diabetic cardiomyopathy.