Abstract 18790: Therapeutic Efficacy of Cardiosphere-Derived Cells in a Transgenic Mouse Model of Nonischemic Dilated Cardiomyopathy

Abstract

Introduction: Cardiosphere-derived cells (CDCs) produce regenerative effects and improve function in the post-infarct setting. However, it is unclear whether CDCs are beneficial in non-ischemic dilated cardiomyopathy (DCM). We tested the effects of CDC transplantation in mice with cardiac-specific Gαq overexpression, which leads to intense myocardial oxidative/nitrosative stress and inflammation. These mice predictably develop progressive cardiac dilation and failure, with accelerated mortality. Methods and Results: A total of 71 mice were investigated in this study. Wild-type syngeneic mouse CDCs (10 5 cells total) or vehicle only were injected intramyocardially at five left ventricular sites in 6-, 8- and 11-week old Gαq mice. Cardiac function deteriorated in vehicle-treated mice over 3 months of follow-up, accompanied by oxidative stress, inflammation and adverse ventricular remodeling. Left ventricular (LV) ejection fraction and LV end-diastolic and end-systolic volumes were progressively worsened over 3 months observational period in vehicle-treated mice compared to CDC-treated group (p<0.05). This was associated with upregulation of reactive oxygen species- and nitric oxide-producing enzymes [NAD(P)H oxidase and inducible nitric oxide synthase], accumulation of proinflammatory oxidant product, 3-Nitrotyrosine, intense infiltration of inflammatory cells [CD68 + macrophages and CD3 + T cells], increased apoptosis and activation of pathologic remodeling pathway, PKC-PKD-CREB. Concomitantly, marked collagen I and III deposition and fibrosis were observed in the vehicle-treated Gαq mouse heart. In contrast, CDCs preserved cardiac function and volumes (p<0.05), and promoted cardiomyocyte cycling (p<0.01) while blunting Gαq-induced oxidative stress, inflammation and fibrosis in the heart. Survival was enhanced by CDCs (p<0.005) in Gαq mice that had been subjected to doxoribicin stress. Conclusions: CDCs reverse fundamental abnormalities in cell signaling, prevent adverse remodeling and improve survival in a mouse model of DCM. These findings motivate testing of CDCs as a potential therapeutic to prevent disease progression in patients with early-stage DCM.