title: Bicuspid aortic valve: phosphorylation of c-Kit and downstream targets are prognostic for future aortopathy.
abstract: OBJECTIVE
  The clinical course of many patients with a bicuspid aortic valve (BAV) is complicated by ascending aortic dilatation. Currently, the indication for aortic surgery is solely based on the aortic diameter and subsequently only a small proportion of BAV patients undergoing valve surgery require concomitant ascending aortic replacement based on these recommendations. Unfortunately, a substantial number of BAV patients still develop aortic dilatation in the future and would potentially benefit from a more aggressive approach towards ascending aortic replacement. We, therefore, designed this study to identify molecular biological markers in the aortic wall predictive of aortopathy in BAV.
  
  
  METHODS
  Ascending aortic wall specimen of BAV (n = 36) and tricuspid aortic valve (TAV) (n = 23), both without and with (>44 mm) dilatation were investigated histologically and immunohistochemically for the expression of markers for vascular remodelling [transforming growth factor (TGF)-β, phosphorylated Smad2, matrix metalloproteinase 9 (MMP9)], cellular differentiation [c-Kit, phosphorylated-c-Kit, hypoxia-inducable factor-1 alpha (HIF1α)] and haemodynamic influences on the aortic wall [endothelial nitric oxide (eNOS)].
  
  
  RESULTS
  All BAV patients showed significantly less inflammation (P < 0.001) and an altered intima/media ratio when compared with TAV patients. The expression of markers of a signalling pathway characteristic for cellular dedifferentiation, as exemplified by the marked expression of c-Kit, phosphorylated c-Kit and HIF1α; in the dilated BAV group was however completely comparable with only a subgroup of the non-dilated BAV (BAb), whereas the remainder of the non-dilated BAV group (BAa) was significantly distinct. This difference between the dilated BAV and BAa was further confirmed in the expression of TGF-β, phosphorylated Smad2, MMP9 and eNOS. Besides the expression pattern, similarity in the dilated BAV and BAb was also noted clinically in the most common variant of commissure position and conjoined raphe of the BAV. Based on these observations, we consider the BAb group a likely candidate for future dilatation as opposed to the BAa group.
  
  
  CONCLUSIONS
  Using a panel of molecular tissue markers, the non-dilated BAV patients can be divided into groups susceptible and non-susceptible to aortopathy.
authors.affiliation: Department of Cardiothoracic Surgery, Leiden University Medical Center, Leiden, Netherlands Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Nimrat
authors.initials: N
authors.lastname: Grewal
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Gittenberger-de Groot
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Marco C
authors.initials: MC
authors.lastname: DeRuiter
authors.affiliation: Department of Cardiothoracic Surgery, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Robert J M
authors.initials: RJ
authors.lastname: Klautz
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Poelmann
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Duim
authors.affiliation: Department of Vascular Surgery, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Johannes H N
authors.initials: JH
authors.lastname: Lindeman
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Wilke M C
authors.initials: WM
authors.lastname: Koenraadt
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, Netherlands Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Monique R M
authors.initials: MR
authors.lastname: Jongbloed
authors.affiliation: Department of Cardiac and Thoracic Vascular Surgery, University of Lübeck, Lübeck, Germany.
authors.forename: Salah A
authors.initials: SA
authors.lastname: Mohamed
authors.affiliation: Department of Cardiac and Thoracic Vascular Surgery, University of Lübeck, Lübeck, Germany.
authors.forename: Hans-Hinrich
authors.initials: HH
authors.lastname: Sievers
authors.affiliation: Department of Cardiothoracic Surgery and Heart Valve Bank, Erasmus University Medical Center, Rotterdam, Netherlands.
authors.forename: Ad J J C
authors.initials: AJ
authors.lastname: Bogers
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, Netherlands m.j.t.h.goumans@lumc.nl.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Goumans
mesh_terms: D000328:Adult; D000368:Aged; D001011:Aorta / Q000737:chemistry / Q000378:metabolism; D001018:Aortic Diseases / Q000175:diagnosis* / Q000378:metabolism; D001021:Aortic Valve / Q000002:abnormalities* / Q000737:chemistry / Q000378:metabolism; D000082882:Bicuspid Aortic Valve Disease; D015415:Biomarkers / Q000737:chemistry* / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D006349:Heart Valve Diseases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000737:chemistry / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D019009:Proto-Oncogene Proteins c-kit
keywords: Aneurysm; Aorta; Congenital; Heart defects; Pathology