title: Histopathology of aortic complications in bicuspid aortic valve versus Marfan syndrome: relevance for therapy?
abstract: Patients with bicuspid aortic valve (BAV) and patients with Marfan syndrome (MFS) are more prone to develop aortic dilation and dissection compared to persons with a tricuspid aortic valve (TAV). To elucidate potential common and distinct pathways of clinical relevance, we compared the histopathological substrates of aortopathy. Ascending aortic wall biopsies were divided in five groups: BAV (n = 36) and TAV (n = 23) without and with dilation and non-dilated MFS (n = 8). General histologic features, apoptosis, the expression of markers for vascular smooth muscle cell (VSMC) maturation, markers predictive for ascending aortic dilation in BAV, and expression of fibrillin-1 were investigated. Both MFS and BAV showed an altered distribution and decreased fibrillin-1 expression in the aorta and a significantly lower level of differentiated VSMC markers. Interestingly, markers predictive for aortic dilation in BAV were not expressed in the MFS aorta. The aorta in MFS was similar to the aorta in dilated TAV with regard to the presence of medial degeneration and apoptosis, while other markers for degeneration and aging like inflammation and progerin expression were low in MFS, comparable to BAV. Both MFS and BAV aortas have immature VSMCs, while MFS and TAV patients have a similar increased rate of medial degeneration. However, the mechanism leading to apoptosis is expected to be different, being fibrillin-1 mutation induced increased angiotensin-receptor-pathway signaling in MFS and cardiovascular aging and increased progerin in TAV. Our findings could explain why angiotensin inhibition is successful in MFS and less effective in TAV and BAV patients.
authors.affiliation: Department of Cardiothoracic Surgery, Leiden University Medical Center, Leiden, The Netherlands.|Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nimrat
authors.initials: N
authors.lastname: Grewal
authors.affiliation: Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Romy
authors.initials: R
authors.lastname: Franken
authors.affiliation: Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Barbara J M
authors.initials: BJ
authors.lastname: Mulder
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Goumans
authors.affiliation: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Johannes H N
authors.initials: JH
authors.lastname: Lindeman
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Cardiology, Leiden University Medical Center, Postal zone S-5-24, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Monique R M
authors.initials: MR
authors.lastname: Jongbloed
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marco C
authors.initials: MC
authors.lastname: DeRuiter
authors.affiliation: Department of Cardiothoracic Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Robert J M
authors.initials: RJ
authors.lastname: Klautz
authors.affiliation: Department of Cardiothoracic Surgery and Heart Valve Bank, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ad J J C
authors.initials: AJ
authors.lastname: Bogers
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Postal zone S-5-24, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.|Department of Biology, Integrative Zoology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Poelmann
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands. a.c.gittenberger-de_groot@lumc.nl.|Department of Cardiology, Leiden University Medical Center, Postal zone S-5-24, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. a.c.gittenberger-de_groot@lumc.nl.
authors.forename: Adriana C Gittenberger-de
authors.initials: AC
authors.lastname: Groot
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000784:Aortic Dissection / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001011:Aorta / Q000737:chemistry / Q000473:pathology*; D001014:Aortic Aneurysm / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001021:Aortic Valve / Q000002:abnormalities* / Q000473:pathology; D017209:Apoptosis; D000082882:Bicuspid Aortic Valve Disease; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D004108:Dilatation, Pathologic; D005260:Female; D000071838:Fibrillin-1 / Q000032:analysis; D006349:Heart Valve Diseases / Q000150:complications* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008382:Marfan Syndrome / Q000150:complications* / Q000473:pathology; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000473:pathology; D009336:Necrosis; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D055815:Young Adult; D054392:Adipokines
chemical_list: D015415:Biomarkers; D000071838:Fibrillin-1; D019009:Proto-Oncogene Proteins c-kit; C000605722:FBN1 protein, human; D054392:Adipokines
keywords: Aneurysm; Aorta; Immunohistochemistry; Molecular biology; Pathology