title: Myocardial Infarction Alters Adaptation of the Tethered Mitral Valve.
abstract: BACKGROUND
  In patients with myocardial infarction (MI), leaflet tethering by displaced papillary muscles induces mitral regurgitation (MR), which doubles mortality. Mitral valves (MVs) are larger in such patients but fibrosis sets in counterproductively. The investigators previously reported that experimental tethering alone increases mitral valve area in association with endothelial-to-mesenchymal transition.
  
  
  OBJECTIVE
  The aim of this study was to explore the clinically relevant situation of tethering and MI, testing the hypothesis that ischemic milieu modifies mitral valve adaptation.
  
  
  METHODS
  Twenty-three adult sheep were examined. Under cardiopulmonary bypass, the papillary muscle tips in 6 sheep were retracted apically to replicate tethering, short of producing MR (tethered alone). Papillary muscle retraction was combined with apical MI created by coronary ligation in another 6 sheep (tethered plus MI), and left ventricular remodeling was limited by external constraint in 5 additional sheep (left ventricular constraint). Six sham-operated sheep were control subjects. Diastolic mitral valve surface area was quantified by 3-dimensional echocardiography at baseline and after 58 ± 5 days, followed by histopathology and flow cytometry of excised leaflets.
  
  
  RESULTS
  Tethered plus MI leaflets were markedly thicker than tethered-alone valves and sham control subjects. Leaflet area also increased significantly. Endothelial-to-mesenchymal transition, detected as α-smooth muscle actin-positive endothelial cells, significantly exceeded that in tethered-alone and control valves. Transforming growth factor-β, matrix metalloproteinase expression, and cellular proliferation were markedly increased. Uniquely, tethering plus MI showed endothelial activation with vascular adhesion molecule expression, neovascularization, and cells positive for CD45, considered a hematopoietic cell marker. Tethered plus MI findings were comparable with external ventricular constraint.
  
  
  CONCLUSIONS
  MI altered leaflet adaptation, including a profibrotic increase in valvular cell activation, CD45-positive cells, and matrix turnover. Understanding cellular and molecular mechanisms underlying leaflet adaptation and fibrosis could yield new therapeutic opportunities for reducing ischemic MR.
authors.affiliation: Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Leducq Transatlantic Mitral Network, Fondation Leducq, Paris, France.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Dal-Bianco
authors.affiliation: Leducq Transatlantic Mitral Network, Fondation Leducq, Paris, France; Center for Excellence in Vascular Biology, Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
authors.affiliation: Leducq Transatlantic Mitral Network, Fondation Leducq, Paris, France; Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Joyce
authors.initials: J
authors.lastname: Bischoff
authors.affiliation: Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: J Luis
authors.initials: JL
authors.lastname: Guerrero
authors.affiliation: Center for Excellence in Vascular Biology, Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jesper
authors.initials: J
authors.lastname: Hjortnaes
authors.affiliation: Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Leducq Transatlantic Mitral Network, Fondation Leducq, Paris, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beaudoin
authors.affiliation: Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Leducq Transatlantic Mitral Network, Fondation Leducq, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Szymanski
authors.affiliation: Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Bartko
authors.affiliation: Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Margo M
authors.initials: MM
authors.lastname: Seybolt
authors.affiliation: Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Handschumacher
authors.affiliation: Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Sullivan
authors.affiliation: Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Garcia
authors.affiliation: Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Adam
authors.initials: A
authors.lastname: Mauskapf
authors.affiliation: Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: James S
authors.initials: JS
authors.lastname: Titus
authors.affiliation: Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jill
authors.initials: J
authors.lastname: Wylie-Sears
authors.affiliation: Center for Excellence in Vascular Biology, Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Whitney S
authors.initials: WS
authors.lastname: Irvin
authors.affiliation: Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Leducq Transatlantic Mitral Network, Fondation Leducq, Paris, France.
authors.forename: Miguel
authors.initials: M
authors.lastname: Chaput
authors.affiliation: Leducq Transatlantic Mitral Network, Fondation Leducq, Paris, France; Departments of Cardiology and Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM Unit 633, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Messas
authors.affiliation: Leducq Transatlantic Mitral Network, Fondation Leducq, Paris, France; Departments of Cardiology and Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM Unit 633, Paris, France.
authors.forename: Albert A
authors.initials: AA
authors.lastname: Hagège
authors.affiliation: Leducq Transatlantic Mitral Network, Fondation Leducq, Paris, France; Departments of Cardiology and Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM Unit 633, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Carpentier
authors.affiliation: Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Leducq Transatlantic Mitral Network, Fondation Leducq, Paris, France; Departments of Cardiology and Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM Unit 633, Paris, France. Electronic address: rlevine@partners.org.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Levine
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D019560:Echocardiography, Three-Dimensional / Q000379:methods; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008943:Mitral Valve / Q000000981:diagnostic imaging / Q000503:physiopathology; D008944:Mitral Valve Insufficiency / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism / Q000473:pathology; D010210:Papillary Muscles / Q000473:pathology*; D012756:Sheep; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D016212:Transforming Growth Factor beta; D020782:Matrix Metalloproteinases
keywords: echocardiography; endothelial-to-mesenchymal transition; inflammation; mitral regurgitation; papillary muscle