Neuregulin-1ß for the Treatment of Post-MI Heart Failure in Type 1 Diabetes
Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) are at heightened risk for the subsequent development of heart failure (HF). Modern treatment strategies (thrombolytic agents, beta blockers, antiplatelets, angiotensin converting enzyme [ACE] inhibitors) have been unable to eliminate the disproportionately higher incidence of post-MI HF experienced by type 1 diabetics. Consequently, a “therapeutic deficit” exists in the treatment and prevention of post-MI HF in patients with type 1 DM. The long-term goals of our pre-clinical testing studies is to facilitate translation to the clinic of novel promising therapies for HF in type 1 DM. In that regard, improved heart function in type 1 diabetic cardiomyopathy rats with chronic heart failure treated with neuregulin (NRG)-1ß suggests that NRG-1ß therapy may be a novel therapeutic approach to limit HF in type 1 DM. While diabetic cardiomyopathy is a contributor to the higher incidence of HF in type 1 DM, MI-related HF accounts for the vast majority of HF events in type 1 diabetics. Thus, the objective of this proposal is to perform additional pre-clinical testing with NRG-1ß to validate its efficacy in ameliorating post-MI induced HF in type 1 diabetic rat hearts. We propose to complete critical pre-clinical efficacy experiments with NRG-1ß using a rat model of HF due to MI by coronary ligation in the presence of streptozotocin (STZ)-induced DM, a well-established type 1 model. Although the main focus of this study is to validate the therapeutic potential of NRG-1ß therapy against HF following MI in an STZ-diabetic rat model, we will also investigate the efficaciousness of NRG-1ß therapy on other end-organ complications, such as vascular, kidney, and peripheral nerve function.

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