Cardiac Beta-Adrenergic Adaptation in Pediatric Heart Failure

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DESCRIPTION (provided by applicant): Functional changes in the 2-adrenergic system play an important role in the pathophysiology of heart failure (HF) in adults. Experimental data has extensively defined many of the components involved in the 2-adrenergic receptor (2-AR) response in HF resulting in a shift of the clinical treatment paradigm to include 2-AR blocker therapy to improve morbidity and mortality. In children with heart failure, however, myocellular changes, including those in the 2-adrenergic system, are poorly understood. This fact proves to be a critical barrier for improving care and clinical outcomes in this vulnerable population. Although circulating catecholamine levels are elevated in both children and adults with HF, the lack of clinical benefit of betablocker (BB) therapy in children with HF is in stark contrast to the overwhelming evidence supporting beneficial BB effects in adults with HF and suggests that there may be important differences between children and adults in the myocellular response of the cardiac 2-adrenergic system to heart failure. Unfortunately, advances in our knowledge are hindered by the difficulty of performing clinical studies in pediatric populations and a lack of animal models specific to pediatric idiopathic cardiomyopathy. The central hypothesis of the current proposal is that the differences in clinical response to BB therapy is a product of differences in the response of the cardiac adrenergic system to HF in children and adults, both at the level of the AR as well as in its intracellular signaling pathways. Therefore the purpose of the current proposal is use our existing adult and pediatric explanted heart tissue banks [1] to identify key myocellular changes in cardiac 2-adrenergic receptors of pediatric patients with HF, and [2] measure the expression of central downstream signaling factors and microRNA effectors that are involved in the 2-adrenergic response in pediatric heart failure patients. In addition, the proposal will develop a mouse model for the response of the pediatric heart to the elevated catecholamine levels present in HF patients. Future investigations will use this model to dissect the molecular mechanisms of increased adrenergic stimulation in children with HF and thereby determine which therapies may be most beneficial in pediatric patients. PUBLIC HEALTH RELEVANCE: Heart failure is a deadly disease in children. In contrast to in adults, the changes that occur in the heart of children with heart failure are poorly understood. The current proposal will improve our understanding of the way a child's heart responds to heart failure so that we can improve medical treatment of this devastating disease.