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.

Consequences of an early catheter‐based intervention on pulmonary artery growth and right ventricular myocardial function in a pig model of pulmonary artery stenosis

“…Importantly, adrenergic function and adaptation are different in the pediatric and adult heart . The physiologic uniqueness of the immature cardiovascular system is underscored by the fact that beta blockers are less effective in pediatric heart failure than in their adult counterparts due to the immature heart downregulation of both β1‐ and β2‐receptors . Since we focused on the juvenile animal, the influence of PA stenosis may impact development of adrenergic signaling and contractile function in the RV in ways that cannot be easily extrapolated from our understanding of adult physiology.…”

“…Importantly, adrenergic function and adaptation are different in the pediatric and adult heart [28]. The physiologic uniqueness of the immature cardiovascular system is underscored by the fact that beta blockers are less effective in pediatric heart failure [29,30] than in their adult counterparts due to the immature heart downregulation of both b1and b2-receptors [31].…”

Age-Related Differences in Phosphodiesterase Activity and Effects of Chronic Phosphodiesterase Inhibition in Idiopathic Dilated Cardiomyopathy

“…32 Protein was isolated from 10- to 25-mg frozen LV tissue in isoelectric focusing buffer homogenized at 4°C as described. 33 Serine 16 (Ser16) PLB phosphorylation (pPLB) (A010-12 - Badrilla) and total PLB (05-205 - Millipore) were quantified on separate blots and normalized to GAPDH (Santa Cruz Biotechnology). PLB is phosphorylated at the Ser16 residue by protein kinase A, which is activated by cAMP.…”

Acute isoproterenol leads to age-dependent arrhythmogenesis in guinea pigs

“…REVEAL LINQ Implantable Cardiac Monitors (Medtronic, Minneapolis, MN) were placed into the pocket on the animal's upper left side. Osmotic pumps (2ML1, 2ML2, and 2ML4, Alzet, Cupertino, CA) containing either saline (control) or ISO (16 or 32 mg•kg Ϫ1 •day Ϫ1 , Sigma-Aldrich) were implanted on the upper right side as previously described (58,60). The incisions were closed with staples.…”

“…Protein was isolated from 10 -20 mg of frozen left ventricular tissue in isoelectric focusing buffer (8 M urea, 2.5 M thiourea, 4% CHAPS, 2 mM EDTA, 1 mM DTT, and 1% TBP) with protease and phosphatase inhibitors and homogenized at 4°C as previously described (60). Protein concentration was determined using the Bradford assay (Bio-Rad).…”