title: The effects of mitral regurgitation alone are sufficient for leaflet remodeling.
abstract: BACKGROUND
  Although chronic mitral regurgitation results in adverse left ventricular remodeling, its effect on the mitral valve leaflets per se is unknown. In a chronic ovine model, we tested whether isolated mitral regurgitation alone was sufficient to remodel the anterior mitral leaflet.
  
  
  RESULTS
  Twenty-nine sheep were randomized to either control (CTRL, n=11) or experimental (HOLE, n=18) groups. In HOLE, a 2.8- to 4.8-mm diameter hole was punched in the middle scallop of the posterior mitral leaflet to create "pure" mitral regurgitation. At 12 weeks, the anterior mitral leaflet was analyzed immunohistochemically to assess markers of collagen and elastin synthesis as well as matrix metalloproteinases and proteoglycans. A semiquantitative grading scale for characteristics such as intensity and delineation of stain between layers was used to quantify differences between HOLE and CTRL specimens across the heterogeneous leaflet structure. At 12 weeks, mitral regurgitation grade was greater in HOLE versus CTRL (3.0+/-0.8 versus 0.4+/-0.4, P<0.001). In HOLE anterior mitral leaflet, saffron-staining collagen (Movat) decreased, consistent with an increase in matrix metalloproteases throughout the leaflet. Type III collagen expression was increased in the midleaflet and free edge and expression of prolyl-4-hydroxylase (indicating collagen synthesis) was increased in the spongiosa layer. The proteoglycan decorin, also involved in collagen fibrillogenesis, was increased compared with CTRL (all P</=0.05).
  
  
  CONCLUSIONS
  In HOLE anterior mitral leaflet, the increased expression of proteins related to collagen synthesis and matrix degradation suggests active matrix turnover. These are the first observations showing that regurgitation alone can stimulate mitral leaflet remodeling. Such leaflet remodeling needs to be considered in reparative surgical techniques.
authors.affiliation: Bioengineering, Rice University, PO Box 1892-MS142, Houston, TX 77251-1892, USA.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Stephens
authors.forename: Tom C
authors.initials: TC
authors.lastname: Nguyen
authors.forename: Akinobu
authors.initials: A
authors.lastname: Itoh
authors.forename: Neil B
authors.initials: NB
authors.lastname: Ingels
authors.forename: D Craig
authors.initials: DC
authors.lastname: Miller
authors.forename: K Jane
authors.initials: KJ
authors.lastname: Grande-Allen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis; D058575:Decorin; D004452:Echocardiography; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008943:Mitral Valve / Q000378:metabolism / Q000503:physiopathology*; D008944:Mitral Valve Insufficiency / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D012756:Sheep; D013194:Staining and Labeling; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D003094:Collagen; D004549:Elastin; D011393:Procollagen-Proline Dioxygenase; D020782:Matrix Metalloproteinases