Published online before print July 13, 2009, doi: 10.1161/CIRCULATIONAHA.108.846782
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(Circulation. 2009;120:334-342.)
© 2009 American Heart Association, Inc.
Valvular Heart Disease |
Active Adaptation of the Tethered Mitral Valve
Insights Into a Compensatory Mechanism for Functional Mitral Regurgitation
From the Cardiac Ultrasound Laboratory (J.P.D., M.D.H., R.A.L.) and Surgical Cardiovascular Laboratory (J.L.G., S.S., B.J., J.T.), Massachusetts General Hospital, Harvard Medical School, Boston; Vascular Biology Program (J.W.-S., J.B.) and Department of Surgery (J.B.), Children’s Hospital Boston and Harvard Medical School, Boston, Mass; Center for Molecular Imaging Research (E.A., Y.I.), Massachusetts General Hospital and Harvard Medical School, Charlestown; Department of Cardiovascular Surgery, Pompidou Hospital, and INSERM Unit 633, Paris, France (A.C.); and Fondation Leducq, Paris, France (J.P.D., E.A., J.B., R.A.L., A.C.).
Correspondence to Robert A. Levine, MD, Massachusetts General Hospital, Cardiac Ultrasound Laboratory, 55 Fruit St, Yawkey 5068, Boston, MA 02114. E-mail rlevine{at}partners.org
Received December 29, 2008; accepted May 13, 2009.
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.
Methods and 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 cm2 (17±10%) from 14.3±1.9 to 16.7±1.9 cm2 (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 
-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. -Smooth muscle actin–positive cells appeared in the atrial endothelium, penetrating into the interstitium, with increased collagen deposition. Thickened chordae showed endothelial and subendothelial -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.
CLINICAL PERSPECTIVE
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Clinical Summaries
Circulation 2009 120: 267-268.[Extract] [Full Text]
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