title: Potential Molecular Mechanism of Retrograde Aortic Arch Stenosis in the Hybrid Approach to Hypoplastic Left Heart Syndrome.
abstract: BACKGROUND
  The hybrid palliation for hypoplastic left heart syndrome has emerged as an alternative approach to the Norwood procedure. The development of patent ductus arteriosus (PDA) in-stent stenosis can cause retrograde aortic arch stenosis (RAAS), leading to significant morbidity. This study aimed to identify potential mechanisms of PDA in-stent stenosis contributing to RAAS.
  
  
  METHODS
  Tissues from stented PDAs were collected from 17 patients undergoing comprehensive stage II repair between 2009 and 2014. Patients requiring RAAS intervention based on cardiology-surgery consensus were defined as RAAS(+) (n = 10), whereas patients without any RAAS intervention were defined as RAAS(-) (n = 7). Tissues were examined by quantitative polymerase chain reaction analysis for vascular smooth muscle cell (VSMC) differentiation and proliferation markers.
  
  
  RESULTS
  Patient characteristics were hypoplastic left heart syndrome with aortic atresia in 6 and with aortic stenosis in 3; unbalanced atrioventricular canal in 3; double-inlet left ventricle/transposition of the great arteries in 3; and double-outlet right ventricle in 2. VSMC differentiation markers (β-actin, SM22, and calponin) and signaling pathways for VSMC modulation (transforming growth factor-β1, Notch, and platelet derived growth factor-BB) were significantly higher in the RAAS(+) than in RAAS(-) patients. The proliferation marker Ki67 was increased in RAAS(+) patients. Cell cycle markers were comparable in both groups.
  
  
  CONCLUSIONS
  Increased VSMC differentiation and proliferation markers suggest a mechanism for inward neointima formation of the PDA in RAAS. The apparent lack of change in cell cycle markers is contrary to coronary artery in-stent stenosis, suggesting further targets should be examined. Combined primary in vitro PDA cell culture and proteomics can be strong tools to elucidate targets to reduce PDA in-stent stenosis for RAAS in the future.
authors.affiliation: The Heart Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Narutoshi
authors.initials: N
authors.lastname: Hibino
authors.affiliation: The Heart Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Cismowski
authors.affiliation: The Heart Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Brenda
authors.initials: B
authors.lastname: Lilly
authors.affiliation: The Heart Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Cardiothoracic Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Patrick I
authors.initials: PI
authors.lastname: McConnell
authors.affiliation: The Heart Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Cardiothoracic Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Shinoka
authors.affiliation: The Heart Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: John P
authors.initials: JP
authors.lastname: Cheatham
authors.affiliation: The Heart Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Lucchesi
authors.affiliation: The Heart Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Cardiothoracic Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Galantowicz
authors.affiliation: The Heart Center, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio. Electronic address: aaron.trask@nationwidechildrens.org.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Trask
mesh_terms: D001024:Aortic Valve Stenosis / Q000209:etiology* / Q000235:genetics; D006348:Cardiac Surgical Procedures; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004374:Ductus Arteriosus, Patent / Q000209:etiology* / Q000235:genetics; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000601:surgery*; D007231:Infant, Newborn; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D011183:Postoperative Complications / Q000209:etiology* / Q000235:genetics; D015607:Stents