title: Cellular and Extracellular Matrix Basis for Heterogeneity in Mitral Annular Contraction.
abstract: OBJECTIVE
  Regional heterogeneity in mitral annular contraction, which is generally ascribed to the fibrous vs. muscular annular composition, ensures proper leaflet motion and timing of coaptation. It is unknown whether the fibroblast-like cells in the annulus modulate this heterogeneity, even though valvular interstitial cells (VICs) can be mechanically "activated."
  
  
  METHODS
  Fourteen sheep underwent implantation of radiopaque markers around the mitral annulus defining four segments: septal (SEPT), lateral (LAT), and anterior (ANT-C) and posterior (POST-C) commissures. Segmental annular contraction was calculated using biplane videofluoroscopy. Immunohistochemistry of annular cross sections assessed regional matrix content, matrix turnover, and cell phenotype. Micropipette aspiration measured the Young's modulus of the leaflets adjacent to the myocardial border.
  
  
  RESULTS
  Whereas SEPT contained more collagen I and III, LAT demonstrated more collagen and elastin turnover as shown by greater decorin, lysyl oxidase, and matrix metalloprotease (MMP)-13 and smooth muscle alpha-actin (SMaA). This greater matrix turnover paralleled greater annular contraction in LAT vs. SEPT (22.5% vs. 4.1%). Similarly, POST-C had more SMaA and MMP13 than ANT-C, consistent with greater annular contraction in POST-C (18.8% vs. 11.1%). Interestingly, POST-C had the greatest effective modulus, significantly higher than LAT.
  
  
  CONCLUSIONS
  These data suggest that matrix turnover by activated VICs relates to annular motion heterogeneity, maintains steady-state mechanical properties in the annulus, and could be a therapeutic target when annular motion is impaired. Conversely, alterations in this heterogeneous annular contraction, whether through disease or secondary to ring annuloplasty, could disrupt this normal pattern of cell-mediated matrix remodeling and further adversely impact mitral valve function.
authors.affiliation: Dept. of Bioengineering, Rice University, Houston, TX ; Dept. of Cardiothoracic Surgery, Columbia University School of Medicine, New York, NY.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Stephens
authors.affiliation: Dept. of Bioengineering, Rice University, Houston, TX.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Fahrenholtz
authors.affiliation: Dept. of Bioengineering, Rice University, Houston, TX.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Connell
authors.affiliation: Dept. of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA ; Dept. of Cardiothoracic Surgery, Meijer Heart and Vascular Institute at Spectrum Health, Grand Rapids, MI.
authors.forename: Tomasz A
authors.initials: TA
authors.lastname: Timek
authors.affiliation: Dept. of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA.
authors.forename: George T
authors.initials: GT
authors.lastname: Daughters
authors.affiliation: Dept. of Bioengineering, Rice University, Houston, TX.
authors.forename: Joyce J
authors.initials: JJ
authors.lastname: Kuo
authors.affiliation: Dept. of Bioengineering, Rice University, Houston, TX.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Patton
authors.affiliation: Dept. of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA ; Dept. of Cardiovascular Physiology and Biophysics, Research Institute, Palo Alto Medical Foundation, Palo Alto, CA.
authors.forename: Neil B
authors.initials: NB
authors.lastname: Ingels
authors.affiliation: Dept. of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA ; Dept. of Cardiovascular Physiology and Biophysics, Research Institute, Palo Alto Medical Foundation, Palo Alto, CA.
authors.forename: D Craig
authors.initials: DC
authors.lastname: Miller
authors.affiliation: Dept. of Bioengineering, Rice University, Houston, TX.
authors.forename: K Jane
authors.initials: KJ
authors.lastname: Grande-Allen
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D058385:Cardiac Valve Annuloplasty / Q000295:instrumentation; D003094:Collagen / Q000378:metabolism; D003287:Contrast Media / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005471:Fluoroscopy / Q000379:methods; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008943:Mitral Valve / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D008944:Mitral Valve Insufficiency / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012756:Sheep / Q000601:surgery
chemical_list: D000199:Actins; D003287:Contrast Media; D003094:Collagen; D020782:Matrix Metalloproteinases
keywords: annular contraction; collagen; extracellular matrix; matrix metalloproteases; mitral annulus