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.

Public Health Relevance

Heart failure is a deadly disease in children. In contrast to what is observed 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, providing a basis for targeted medical treatment specific to children and thereby improve the outcome of this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107715-03
Application #
8588989
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Kaltman, Jonathan R
Project Start
2011-12-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$495,530
Indirect Cost
$134,088
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
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; 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
Brown, David A; Perry, Justin B; Allen, Mitchell E et al. (2017) Expert consensus document: Mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol 14:238-250
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
Tatman, Philip D; Woulfe, Kathleen C; Karimpour-Fard, Anis et al. (2017) Pediatric dilated cardiomyopathy hearts display a unique gene expression profile. JCI Insight 2:
Nakano, Stephanie J; Nelson, Penny; Sucharov, Carmen C et al. (2016) Myocardial Response to Milrinone in Single Right Ventricle Heart Disease. J Pediatr 174:199-203.e5
Dow, Caitlin A; Templeton, Danielle L; Lincenberg, Grace M et al. (2016) Elevations in C-reactive protein and endothelin-1 system activity in humans. Life Sci 159:66-70
Miyamoto, Shelley D; Karimpour-Fard, Anis; Peterson, Valencia et al. (2015) Circulating microRNA as a biomarker for recovery in pediatric dilated cardiomyopathy. J Heart Lung Transplant 34:724-33
Stauffer, Brian L; Dockstader, Karen; Russell, Gloria et al. (2015) Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner. Biochem Biophys Res Commun 462:131-7

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