Project 451648

Diabetes mellitus is a growing epidemic that is associated with severe cardiovascular complications. Included amongst these is atrial fibrillation (the most common cardiac arrhythmia), which is a major cause of increased morbidity and mortality in type 1 and type 2 diabetes. Despite these links, the basis for atrial fibrillation in diabetes is poorly understood. Our first objective is to determine the specific causes of atrial fibrillation in diabetes mellitus, which are likely unique from atrial fibrillation in other forms of cardiovascular disease. Current therapeutic approaches for atrial fibrillation in diabetic patients are severely limited; therefore, our second objective is to discover new approaches to prevent and treat atrial fibrillation in diabetes mellitus. Our recent studies demonstrate that atrial fibrillation in mouse models of type 1 and type 2 diabetes occurs as a result of a number of changes in heart. These include changes in the electrical properties of the muscle cells of the heart as well as a buildup of scar tissue in the heart. In our proposed studies we will determine how each of these leads to the occurrence of atrial fibrillation and which mechanisms are most important in allowing this arrhythmia to occur. We have also discovered new approaches for the prevention of atrial fibrillation in type 1 and type 2 diabetes mellitus by targeting insulin signaling and a family of hormones called incretins. Our studies will continue to investigate these approaches to prevent atrial fibrillation in diabetes. Our experiments are performed using a wide range of powerful approaches from the molecular and cellular levels to the intact animal. Our proposed studies will provide critical insight into the basis for atrial fibrillation, and new approaches to prevent it, in diabetes mellitus.