title: β-Adrenergic receptor antagonism in mice: a model for pediatric heart disease.
abstract: Children with heart failure are treated with similar medical therapy as adults with heart failure. In contrast to adults with heart failure, these treatment regiments are not associated with improved outcomes in children. Recent studies have demonstrated age-related pathophysiological differences in the molecular mechanisms of heart failure between children and adults. There are no animal models of pediatric cardiomyopathy to allow mechanistic studies. The purpose of the current experiments was to develop a mouse model of pediatric heart disease and test whether the influence of β-adrenergic receptor (β-AR) antagonism could be modeled in this system. We hypothesized that isoproterenol treatment of young mice would provide a model system of cardiac pathology, and that nonselective β-AR blockade would provide benefit in adult, but not young, mice, similar to clinical trial data. We found that isoproterenol treatment (through osmotic minipump implantation) of young and adult mice produced similar degrees of cardiac hypertrophy and recapitulated several age-related molecular abnormalities in human heart failure, including phospholamban phosphorylation and β-AR expression. We also found that nonselective β-AR blockade effectively prevented pathological cardiac growth and collagen expression in the adult but not young mice, and that selective β1-AR blockade was effective in both young and adult isoproterenol-treated mice. In conclusion, we have developed the first model system for β-AR-mediated pediatric heart disease. Furthermore, we have generated novel data suggesting beneficial effects of selective β1-AR blockade in the pediatric heart.
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado;
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Sucharov
authors.forename: Jamie G
authors.initials: JG
authors.lastname: Hijmans
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Sobus
authors.forename: William F A
authors.initials: WF
authors.lastname: Melhado
authors.forename: Shelley D
authors.initials: SD
authors.lastname: Miyamoto
authors.forename: Brian L
authors.initials: BL
authors.lastname: Stauffer
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D002648:Child; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol
keywords: antagonist; heart failure; pediatric; phospholamban; β-adrenergic receptor