title: Gene expression and β-adrenergic signaling are altered in hypoplastic left heart syndrome.
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.
authors.affiliation: Department of Pediatrics and Children's Hospital Colorado, Aurora, Colorado. Electronic address: shelley.miyamoto@childrenscolorado.org.
authors.forename: Shelley D
authors.initials: SD
authors.lastname: Miyamoto
authors.affiliation: Division of Cardiology, University of Colorado Denver School of Medicine, Aurora, Colorado; Division of Cardiology, Denver Health and Hospital Authority, Denver, Colorado.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Stauffer
authors.affiliation: Division of Cardiology, University of Colorado Denver School of Medicine, Aurora, Colorado.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Polk
authors.affiliation: Division of Cardiology, University of Colorado Denver School of Medicine, Aurora, Colorado.
authors.forename: Allen
authors.initials: A
authors.lastname: Medway
authors.affiliation: Department of Pediatrics and Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Matthew
authors.initials: M
authors.lastname: Friedrich
authors.affiliation: Department of Pediatrics and Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Kurt
authors.initials: K
authors.lastname: Haubold
authors.affiliation: Division of Cardiology, University of Colorado Denver School of Medicine, Aurora, Colorado.
authors.forename: Valencia
authors.initials: V
authors.lastname: Peterson
authors.affiliation: Department of Pediatrics and Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Karin
authors.initials: K
authors.lastname: Nunley
authors.affiliation: Division of Cardiology, University of Colorado Denver School of Medicine, Aurora, Colorado.
authors.forename: Penny
authors.initials: P
authors.lastname: Nelson
authors.affiliation: Division of Cardiology, University of Colorado Denver School of Medicine, Aurora, Colorado.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sobus
authors.affiliation: Department of Pediatrics and Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
authors.affiliation: Division of Cardiology, University of Colorado Denver School of Medicine, Aurora, Colorado.
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Sucharov
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D016027:Heart Transplantation; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics* / Q000503:physiopathology* / Q000601:surgery; D007223:Infant; D008297:Male; D009206:Myocardium / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D018497:Ventricular Dysfunction, Right / Q000235:genetics / Q000503:physiopathology
chemical_list: D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V
keywords: gene expression; hypoplastic left heart syndrome; right ventricle; β-adrenergic receptor system