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.
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.
| Miyamoto, Shelley D; Sucharov, Carmen C; Woulfe, Kathleen C (2018) Differential Response to Heart Failure Medications in Children. Prog Pediatr Cardiol 49:27-30 |
| Woulfe, Kathleen C; Siomos, Austine K; Nguyen, Hieu et al. (2017) Fibrosis and Fibrotic Gene Expression in Pediatric and Adult Patients With Idiopathic Dilated Cardiomyopathy. J Card Fail 23:314-324 |
| Nakano, Stephanie J; Sucharov, Juliana; van Dusen, Robert et al. (2017) Cardiac Adenylyl Cyclase and Phosphodiesterase Expression Profiles Vary by Age, Disease, and Chronic Phosphodiesterase Inhibitor Treatment. J Card Fail 23:72-80 |
| Medina, Elizabeth; Sucharov, Carmen C; Nelson, Penny et al. (2017) Molecular Changes in Children with Heart Failure Undergoing Left Ventricular Assist Device Therapy. J Pediatr 182:184-189.e1 |
| Nakano, Stephanie J; Siomos, Austine K; Garcia, Anastacia M et al. (2017) Fibrosis-Related Gene Expression in Single Ventricle Heart Disease. J Pediatr 191:82-90.e2 |
| Nakano, Stephanie J; Miyamoto, Shelley D; Movsesian, Matthew et al. (2015) Age-related differences in phosphodiesterase activity and effects of chronic phosphodiesterase inhibition in idiopathic dilated cardiomyopathy. Circ Heart Fail 8:57-63 |
| Miyamoto, Shelley D; Stauffer, Brian L; Nakano, Stephanie et al. (2014) Beta-adrenergic adaptation in paediatric idiopathic dilated cardiomyopathy. Eur Heart J 35:33-41 |
| Miyamoto, Shelley D; Stauffer, Brian L; Polk, Jeremy et al. (2014) Gene expression and ?-adrenergic signaling are altered in hypoplastic left heart syndrome. J Heart Lung Transplant 33:785-93 |
| Stauffer, Brian L; Russell, Gloria; Nunley, Karin et al. (2013) miRNA expression in pediatric failing human heart. J Mol Cell Cardiol 57:43-6 |
| Sucharov, Carmen C; Hijmans, Jamie G; Sobus, Rebecca D et al. (2013) *-Adrenergic receptor antagonism in mice: a model for pediatric heart disease. J Appl Physiol (1985) 115:979-87 |
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