title: Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation.
abstract: BACKGROUND
  In patients with left ventricular infarction or dilatation, leaflet tethering by displaced papillary muscles frequently induces mitral regurgitation, which doubles mortality. Little is known about the biological potential of the mitral valve (MV) to compensate for ventricular remodeling. We tested the hypothesis that MV leaflet surface area increases over time with mechanical stretch created by papillary muscle displacement through cell activation, not passive stretching.
  
  
  RESULTS
  Under cardiopulmonary bypass, the papillary muscle tips in 6 adult sheep were retracted apically short of producing mitral regurgitation to replicate tethering without confounding myocardial infarction or turbulence. Diastolic leaflet area was quantified by 3-dimensional echocardiography over 61+/-6 days compared with 6 unstretched sheep MVs. Total diastolic leaflet area increased by 2.4+/-1.3 cm(2) (17+/-10%) from 14.3+/-1.9 to 16.7+/-1.9 cm(2) (P=0.006) with stretch with no change in the unstretched valves despite sham open heart surgery. Stretched MVs were 2.8 times thicker than normal (1.18+/-0.14 versus 0.42+/-0.14 mm; P<0.0001) at 60 days with an increased spongiosa layer. Endothelial cells (CD31(+)) coexpressing alpha-smooth muscle actin were significantly more common by fluorescent cell sorting in tethered versus normal leaflets (41+/-19% versus 9+/-5%; P=0.02), indicating endothelial-mesenchymal transdifferentiation. alpha-Smooth muscle actin-positive cells appeared in the atrial endothelium, penetrating into the interstitium, with increased collagen deposition. Thickened chordae showed endothelial and subendothelial alpha-smooth muscle actin. Endothelial-mesenchymal transdifferentiation capacity also was demonstrated in cultured MV endothelial cells.
  
  
  CONCLUSIONS
  Mechanical stresses imposed by papillary muscle tethering increase MV leaflet area and thickness, with cellular changes suggesting reactivated embryonic developmental pathways. Understanding such actively adaptive mechanisms can potentially provide therapeutic opportunities to augment MV area and reduce ischemic mitral regurgitation.
authors: Massachusetts General Hospital, Cardiac Ultrasound Laboratory, Harvard Medical School, Boston, MA 02114, USA.
authors: Jacob P
authors: JP
authors: Dal-Bianco
authors: Elena
authors: E
authors: Aikawa
authors: Joyce
authors: J
authors: Bischoff
authors: J Luis
authors: JL
authors: Guerrero
authors: Mark D
authors: MD
authors: Handschumacher
authors: Suzanne
authors: S
authors: Sullivan
authors: Benjamin
authors: B
authors: Johnson
authors: James S
authors: JS
authors: Titus
authors: Yoshiko
authors: Y
authors: Iwamoto
authors: Jill
authors: J
authors: Wylie-Sears
authors: Robert A
authors: RA
authors: Levine
authors: Alain
authors: A
authors: Carpentier
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D008943:Mitral Valve / Q000502:physiology*; D008944:Mitral Valve Insufficiency / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D034561:Sheep, Domestic; D014463:Ultrasonography