title: Evaluation of a porcine model of early aortic valve sclerosis.
abstract: BACKGROUND
  Calcific aortic valve disease (CAVD) is associated with significant cardiovascular morbidity. While late-stage CAVD is well-described, early pathobiological processes are poorly understood due to the lack of animal models that faithfully replicate early human disease. Here we evaluated a hypercholesterolemic porcine model of early diet-induced aortic valve sclerosis.
  
  
  METHODS
  Yorkshire swine were fed either a standard or high-fat/high-cholesterol diet for 2 or 5 months. Right coronary aortic valve leaflets were excised and analyzed (immuno)histochemically.
  
  
  RESULTS
  Early human-like proteoglycan-rich onlays formed between the endothelial layer and elastic lamina in the fibrosa layer of valve leaflets, with accelerated formation associated with hypercholesterolemia (P<.05). Lipid deposition was more abundant in hypercholesterolemic swine (P<.001), but was present in a minority (28%) of onlays. No myofibroblasts, MAC387-positive macrophages, or fascin-positive dendritic cells were detected in 2-month onlays, with only scarce myofibroblasts present at 5 months. Cells that expressed osteochondral markers Sox9 and Msx2 were preferentially found in dense proteoglycan-rich onlays (P<.05) and with hypercholesterolemia (P<.05). Features of more advanced human CAVD, including calcification, were not observed in this necessarily short study.
  
  
  CONCLUSIONS
  Early aortic valve sclerosis in hypercholesterolemic swine is characterized by the formation of proteoglycan-rich onlays in the fibrosa, which can occur prior to significant lipid accumulation, inflammatory cell infiltration, or myofibroblast activation. These characteristics mimic those of early human aortic valve disease, and thus the porcine model has utility for the study of early valve sclerosis.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, Ontario, Canada, M5S 3G9.
authors.forename: Krista L
authors.initials: KL
authors.lastname: Sider
authors.affiliation: Department of Animal and Poultry Science, University of Guelph, 50 Stone Road East, Building #70, Guelph, Ontario, Canada, N1G 2W1.
authors.forename: Cuilan
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, Ontario, Canada, M5S 3G9.
authors.forename: Andrea V
authors.initials: AV
authors.lastname: Kwong
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, Ontario, Canada, M5S 3G9.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Mirzaei
authors.affiliation: Department of Animal and Poultry Science, University of Guelph, 50 Stone Road East, Building #70, Guelph, Ontario, Canada, N1G 2W1.
authors.forename: Cornelius F M
authors.initials: CF
authors.lastname: de Langé
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, Ontario, Canada, M5S 3G9; Department of Mechanical and Industrial Engineering, University of Toronto, 5 King's College Road, Toronto, Ontario, Canada, M5S 3G8. Electronic address: c.simmons@utoronto.ca.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Simmons
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D006330:Heart Defects, Congenital / Q000473:pathology*; D006349:Heart Valve Diseases / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D012598:Sclerosis; D034421:Sus scrofa
keywords: Aortic valve sclerosis; Heart valve; Msx2; Porcine; Proteoglycan; Sox9