Shelley D Miyamoto1, Brian L Stauffer2, Jeremy Polk3, Allen Medway3, Matthew Friedrich4, Kurt Haubold4, Valencia Peterson3, Karin Nunley4, Penny Nelson3, Rebecca Sobus3, Kurt R Stenmark4, Carmen C Sucharov3. 1. Department of Pediatrics and Children's Hospital Colorado, Aurora, Colorado. Electronic address: shelley.miyamoto@childrenscolorado.org. 2. Division of Cardiology, University of Colorado Denver School of Medicine, Aurora, Colorado; Division of Cardiology, Denver Health and Hospital Authority, Denver, Colorado. 3. Division of Cardiology, University of Colorado Denver School of Medicine, Aurora, Colorado. 4. Department of Pediatrics and Children's Hospital Colorado, Aurora, Colorado.
Abstract
BACKGROUND: The purpose of the current study was to define the myocellular changes and adaptation of the β-adrenergic receptor (β-AR) system that occur in the systemic right ventricle (RV) of children with hypoplastic left heart syndrome (HLHS). METHODS: Explanted hearts from children with HLHS and non-failing controls were used for this study. HLHS patients were divided into 2 groups: "compensated" (C-HLHS), infants listed for primary transplant with normal RV function and absence of heart failure symptoms, and "decompensated" (D-HLHS), patients listed for transplant after failed surgical palliation with RV failure and/or refractory protein-losing enteropathy or plastic bronchitis. RESULTS: Compared with non-failing control RVs, the HLHS RV demonstrated decreased sarcoplasmic reticulum calcium-adenosine triphosphatase 2a and α-myosin heavy chain (MHC) gene expression, decreased total β-AR due to down-regulation of β1-AR, preserved cyclic adenosine monophosphate levels, and increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity. There was increased atrial natriuretic peptide expression only in the C-HLHS group. Unique to those in the D-HLHS group was increased β-MHC and decreased α-MHC protein expression (MHC isoform switching), increased adenylyl cyclase 5 expression, and increased phosphorylation of the CaMK target site on phospholamban, threonine 17. CONCLUSIONS: The HLHS RV has an abnormal myocardial gene expression pattern, downregulation of β1-AR, preserved cyclic adenosine monophosphate levels, and increased CaMKII activity compared with the non-failing control RV. There is MHC isoform switching, increased adenylyl cyclase 5, and increased phosphorylation of phospholamban threonine 17 only in the D-HLHS group. Although abnormal gene expression and changes in the β-AR system precede clinically evident ventricular failure in HLHS, additional unique adaptations occur in those with HLHS and failed surgical palliation.
BACKGROUND: The purpose of the current study was to define the myocellular changes and adaptation of the β-adrenergic receptor (β-AR) system that occur in the systemic right ventricle (RV) of children with hypoplastic left heart syndrome (HLHS). METHODS: Explanted hearts from children with HLHS and non-failing controls were used for this study. HLHS patients were divided into 2 groups: "compensated" (C-HLHS), infants listed for primary transplant with normal RV function and absence of heart failure symptoms, and "decompensated" (D-HLHS), patients listed for transplant after failed surgical palliation with RV failure and/or refractory protein-losing enteropathy or plastic bronchitis. RESULTS: Compared with non-failing control RVs, the HLHS RV demonstrated decreased sarcoplasmic reticulum calcium-adenosine triphosphatase 2a and α-myosin heavy chain (MHC) gene expression, decreased total β-AR due to down-regulation of β1-AR, preserved cyclic adenosine monophosphate levels, and increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity. There was increased atrial natriuretic peptide expression only in the C-HLHS group. Unique to those in the D-HLHS group was increased β-MHC and decreased α-MHC protein expression (MHC isoform switching), increased adenylyl cyclase 5 expression, and increased phosphorylation of the CaMK target site on phospholamban, threonine 17. CONCLUSIONS: The HLHS RV has an abnormal myocardial gene expression pattern, downregulation of β1-AR, preserved cyclic adenosine monophosphate levels, and increased CaMKII activity compared with the non-failing control RV. There is MHC isoform switching, increased adenylyl cyclase 5, and increased phosphorylation of phospholamban threonine 17 only in the D-HLHS group. Although abnormal gene expression and changes in the β-AR system precede clinically evident ventricular failure in HLHS, additional unique adaptations occur in those with HLHS and failed surgical palliation.
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