title: Characterizing the angiogenic activity of patients with single ventricle physiology and aortopulmonary collateral vessels.
abstract: OBJECTIVE
  Patients with single ventricle congenital heart disease often form aortopulmonary collateral vessels via an unclear mechanism. To gain insights into the pathogenesis of aortopulmonary collateral vessels, we correlated angiogenic factor levels with in vitro activity and angiographic aortopulmonary collateral assessment and examined whether patients with single ventricle physiology have increased angiogenic factors that can stimulate endothelial cell sprouting in vitro.
  
  
  METHODS
  In patients with single ventricle physiology (n = 27) and biventricular acyanotic control patients (n = 21), hypoxia-inducible angiogenic factor levels were measured in femoral venous and arterial plasma at cardiac catheterization. To assess plasma angiogenic activity, we used a 3-dimensional in vitro cell sprouting assay that recapitulates angiogenic sprouting. Aortopulmonary collateral angiograms were graded using a 4-point scale.
  
  
  RESULTS
  Compared with controls, patients with single ventricle physiology had increased vascular endothelial growth factor (artery: 58.7 ± 1.2 pg/mL vs 35.3 ± 1.1 pg/mL, P < .01; vein: 34.8 ± 1.1 pg/mL vs 21 ± 1.2 pg/mL, P < .03), stromal-derived factor 1-alpha (artery: 1901.6 ± 1.1 pg/mL vs 1542.6 ± 1.1 pg/mL, P < .03; vein: 2092.8 pg/mL ± 1.1 vs 1752.9 ± 1.1 pg/mL, P < .02), and increased arterial soluble fms-like tyrosine kinase-1, a regulatory vascular endothelial growth factor receptor (612.3 ± 1.2 pg/mL vs 243.1 ± 1.2 pg/mL, P < .003). Plasma factors and sprout formation correlated poorly with aortopulmonary collateral severity.
  
  
  CONCLUSIONS
  We are the first to correlate plasma angiogenic factor levels with angiography and in vitro angiogenic activity in patients with single ventricle disease with aortopulmonary collaterals. Patients with single ventricle disease have increased stromal-derived factor 1-alpha and soluble fms-like tyrosine kinase-1, and their roles in aortopulmonary collateral formation require further investigation. Plasma factors and angiogenic activity correlate poorly with aortopulmonary collateral severity in patients with single ventricles, suggesting complex mechanisms of angiogenesis.
authors.affiliation: Laboratory of Stem Cell and Neurovascular Biology, Genetics and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; Division of Pediatric Cardiology, Children's National Health System, Washington, DC.
authors.forename: Nefthi
authors.initials: N
authors.lastname: Sandeep
authors.affiliation: Laboratory of Stem Cell and Neurovascular Biology, Genetics and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Division of Pediatric Cardiology, Children's National Health System, Washington, DC.
authors.forename: Kanishka
authors.initials: K
authors.lastname: Ratnayaka
authors.affiliation: Department of Biostatistics & Informatics, Children's National Health System, Washington, DC.
authors.forename: Robert
authors.initials: R
authors.lastname: McCarter
authors.affiliation: Division of Pediatric Cardiology, Children's National Health System, Washington, DC.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Hanumanthaiah
authors.affiliation: Division of Pediatric Cardiology, Children's National Health System, Washington, DC.
authors.forename: Aminata
authors.initials: A
authors.lastname: Bangoura
authors.affiliation: Department of Laboratory Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Laboratory Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Oliver-Danna
authors.affiliation: Division of Pediatric Cardiology, Children's National Health System, Washington, DC.
authors.forename: Linda
authors.initials: L
authors.lastname: Leatherbury
authors.affiliation: Division of Pediatric Cardiology, Children's National Health System, Washington, DC.
authors.forename: Joshua
authors.initials: J
authors.lastname: Kanter
authors.affiliation: Laboratory of Stem Cell and Neurovascular Biology, Genetics and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. Electronic address: mukoyamay@mail.nih.gov.
authors.forename: Yoh-Suke
authors.initials: YS
authors.lastname: Mukouyama
mesh_terms: D000293:Adolescent; D042501:Angiogenic Proteins / Q000097:blood*; D001011:Aorta / Q000503:physiopathology*; D001027:Aortography; D016022:Case-Control Studies; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003097:Collateral Circulation; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006330:Heart Defects, Congenital / Q000097:blood* / Q000175:diagnosis / Q000503:physiopathology; D006801:Humans; D007223:Infant; D008297:Male; D018919:Neovascularization, Physiologic; D011651:Pulmonary Artery / Q000503:physiopathology*; D011652:Pulmonary Circulation; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood
chemical_list: D042501:Angiogenic Proteins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: aortopulmonary collateral; congenital heart disease; single ventricle