B2-Adrenergic Modulation of Mitochondrial Stress to Prevent Sudden Cardiac Death in Diabetes

β2-Adrenergic Modulation of Mitochondrial Stress to Prevent Sudden Cardiac Death in Diabetes Abstract Sudden cardiac death (SCD) remains a leading cause of mortality in individuals with diabetes. Both type 1 and type 2 diabetes markedly increase SCD risk, and recent epidemiological data identify hypoglycemia as a prevalent and underappreciated contributor. However, the mechanisms linking recurrent hypoglycemia (RH) to lethal arrhythmias are poorly understood. Although short-term RH can precondition and transiently suppress arrhythmias, emerging evidence indicates that prolonged RH becomes maladaptive, promoting cardiac dysfunction and electrical instability. The biological mechanisms governing this transition, and how they may be therapeutically targeted, remain undefined. Mitochondrial function is a central determinant of cardiac electrophysiology and arrhythmogenesis. While adaptive increases in mitochondrial oxidative capacity may initially support energetic demand during hypoglycemic stress, sustained mitochondrial hypercompensation is predicted to disrupt redox balance and promote arrhythmogenic vulnerability. β2-adrenergic signaling has emerged as a cardioprotective pathway under chronic stress, yet its role in constraining hypoglycemia-induced mitochondrial remodeling in the diabetic heart has not been established. We hypothesize that recurrent hypoglycemia drives maladaptive mitochondrial hyperactivation that increases susceptibility to sudden cardiac death, and that β2- adrenergic signaling restrains pathological mitochondrial stress responses to mitigate hypoglycemia-associated SCD risk. Aim 1 will define how β2-adrenergic signaling modulates mitochondrial bioenergetics, cardiac function, and electrical stability during short-term RH in STZ-diabetic rats using β2 agonism with formoterol with and without β1 blockade to isolate β2-specific effects. Aim 2 will determine whether long-term β2 activation prevents maladaptive cardiac remodeling during prolonged RH. This project will identify mitochondrial hypercompensation and its transition to dysfunction as a mechanistic link between RH and SCD and establish β2-adrenergic signaling as a novel therapeutic axis to prevent hypoglycemia-associated cardiac death in diabetes.