Abstract 11220: Cardiac Bridging Integrator 1 Gene Therapy Rescues Diabetic Cardiomyopathy in Mice

Abstract

Introduction: Diabetes is a major cause of heart failure with preserved ejection fraction (HFpEF), which has limited diagnostic tools and therapeutic options. Abnormal remodeling in the t-tubule calcium handling cardiac bridging integrator 1 (cBIN1)-microdomains has emerged as key to the pathophysiology of failing cardiomyocytes, which can be targeted for cardiac functional improvement. It remains unclear whether cBIN1 replacement therapy is effective in restoring cardiac function in diabetic HFpEF. Hypothesis: We hypothesized that cBIN1 gene therapy rescues diastolic failure in mice with diabetic cardiomyopathy. Methods: 9-wks old male and female db/db mice that received retro-orbital injection of 1x10 11 vg of AAV9 transducing GFP or cBIN1 were compared to non-diabetic control db/m littermates injected with AAV9-GFP (N = 16 mice per group). Mice were terminated 8-wks later for tissue acquisition, imaging, as well as biochemical analysis. Echocardiography, exercise tolerance, and plasma cBIN1 score (CS, an inverse index of plasma cBIN1 concentration) were obtained before and after gene therapy. Results: db/db mice developed diastolic failure with reduced E/A, increased E/e’, exercise intolerance, and cardiac hypertrophy with reduced tissue cBIN1 levels and corresponding elevations in plasma CS. Supporting our hypothesis, AAV9-cBIN1 normalized E/A and E/e’ and improved exercise tolerance in db/db mice, which can be distinguished by plasma CS as an inverse marker of cBIN1-microfolds and cardiomyocyte remodeling (Figure 1). Preservation of cBIN1-microdomains in db/db cardiomyocytes reorganized functional SERCA2a and rescued mitochondrial respiration with diminished oxidative stress. Conclusions: Exogenous cBIN1 normalizes lusitropic function of diabetic hearts through microdomain-organized effective calcium handling and mitochondrial respiration. cBIN1 gene therapy is a new and effective method for guided treatment of diabetic HFpEF.