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. We have previously demonstrated differences in regulation of 2-ARs between adults and children with heart failure that may explain the age-related discrepancies in BB clinical trial results. These findings suggest that the differences between children and adults in the myocellular response of the cardiac 2- adrenergic system to heart failure could have important clinical implications. 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 dilated cardiomyopathy. The central hypothesis of the current proposal is that the differential clinical response to BB therapy in children and adults with heart failure is a product of age-related differences in the regulation of the cardiac adrenergic system. These molecular changes occur at both at the level of the AR as well as in its intracellular signaling pathways and influence function at the myocardial and sarcomeric levels. Therefore the purpose of the current proposal is to use our existing adult and pediatric explanted heart tissue banks to: [1] identify key myocellular changes in signaling cascade and effector proteins downstream from cardiac 2-adrenergic receptors of pediatric patients with HF and in a mouse model of pediatric HF, [2] determine mechanisms for the regulation of 2-adrenergic receptor expression in the pediatric heart, and [3] determine differences in the myocardial mechanical response to adrenergic signaling in isolated pediatric cardiac sarcomeres and 2-adrenergic receptor subtype contribution to force generation in isolated trabeculae between failing and nonfailing pediatric hearts. Understanding the unique pathophysiology of heart failure in children will facilitate novel clinical trials to improve clinical outcomes in this vulnerable population.

R01HL107715

2011-12-01

2017-11-30