1053 PHARMACOLOGICAL REDUCTION OF OXIDATIVE STRESS COUNTERACTS CARDIAC DISFUNCTION IN A MURINE MODEL OF DYSTROPHIC CARDIOMIOPATHY


 
 
 Dystrophic cardiomyopathy culminates in heart failure and arrhythmias and is a major burden for Duchenne muscular dystrophy (DMD) patients. Mechanism-driven therapies designed to contrast the development of muscle and cardiac dysfunction are still missing. Antioxidant treatments counteract myocyte injury in mdx mice, a genetic model of DMD, supporting the possible role of enhanced reactive oxygen species (ROS) in the pathophysiology of muscular dystrophies. Previous evidence shows that monoamine oxidases (MAO) represent an important source of ROS, thus contributing to cardiomyocyte damage and dysfunction in different models of heart disease.
 
 
 
 we tested whether MAO-induced ROS formation contributes to the progression of pathology in dystrophic hearts.
 
 
 
 wild type (WT) and mdx mice at 3 and 12 months of age were employed. Cardiac function was determined by echocardiography measuring: fractional shortening, ejection fraction and left ventricle strain. Cardiac structure and fibrosis amount were assessed through histology (H&E, Masson's Trichrome). To test whether reduction in ROS burden could ameliorate cardiac structure and function in mdx mice, MAO-B inhibitor safinamide was administered to WT and mdx mice respectively at 3 and 12 months of age.
 
 
 
 We found that fractional shortening (FS) and ejection fraction (EF) were reduced by 1.2- and 2-fold at 3 and 12 months of age, respectively, in mdx mice vs their WT counterpart. In addition, left ventricle (LV) strain was impaired in mdx mice already at 3 months of age. This functional impairment was accompanied by a 5-fold increase in fibrosis in mdx hearts, evident already at 3 months. Safinamide administration for 30 days, led to a significant improvement of FS, EF and LV strain in mdx mice. Half of the mice in the safinamide cohort showed reduced levels of myocardial fibrosis.
 
 
 
 Taken together, these results suggest that pharmacological MAO-B inhibition improves cardiac function in a genetic model of DMD and may represent a clinically relevant target for the treatment of dystrophic cardiomyopathies.
