Abstract 18448: Beta-adrenergic Receptors are Downregulated in Hypoplastic Left Heart Syndrome
Failure of the systemic right ventricle (RV) in children with Hypoplastic Left Heart Syndrome (HLHS) is a leading cause of death and indication for heart transplantation. In adult heart failure studies, the benefits of β-blocker therapy are well established and β-adrenergic receptor (β-AR) expression is well described. In adult heart failure, total β-AR expression is decreased by 35% and the β1-AR is typically decreased by 50%. In a recent trial of β-blocker therapy in children with symptomatic heart failure, those with a systemic RV (ie HLHS) actually demonstrated a trend towards a detrimental effect in response to carvedilol. Gene and protein expression in the RV of children with HLHS are unknown. The purpose of the current study was to determine changes in the myocardial expression of genes associated with remodeling and β-ARs in HLHS. We hypothesized that a pathologic gene profile and β-AR downregulation would be present. Gene expression in RV tissue from explanted HLHS and non-failing (NF) donor RV from children (HLHS: 26, age: 3 weeks-7 years; NF: 14, age: 1.3-16 years) was determined by RT-PCR for ANP, α-myosin heavy chain (α-MHC) and SERCA. Total β-AR protein density and subtype expression was determined by 125I-iodocyanopindolol (ICYP) saturation curves and betaxolol-ICYP competition curves, respectively (HLHS: 5, NF RV: 4). HLHS RV tissue demonstrated increased ANP (4.5 fold, p<0.005) and decreased α-MHC (10-fold, p<0.005) and SERCA (2.2 fold, p<0.05) mRNA expression compared to NF RV. Total β-AR protein density in HLHS RV was ∼68% lower in comparison to NF RV, p<0.0001. The ratio of β1:β2-AR was altered (49±21:51±21 vs 82±7:18±7) and the amount of β1-AR protein was significantly lower (24.6±21 vs 129±7fmol/mg, p<0.001) in HLHS RV compared to NF RV. The myocardial gene expression pattern in HLHS RV resembles a failing phenotype indicative of pathologic remodeling with increased ANP and decreased α-MHC and SERCA expression. There is marked downregulation of β-ARs in the HLHS RV, primarily due to an 80% decrease in β1-AR. In conclusion, additional pharmacologic blockade on top of already remarkable β-AR downregulation in a systemic RV may account for the lack of response to β-blocker therapy in children with HLHS.
- © 2010 by American Heart Association, Inc.