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(Circulation. 2009;120:S112-S119.)
© 2009 American Heart Association, Inc.

Surgery for Valvular Heart Disease

Significant Changes in Mitral Valve Leaflet Matrix Composition and Turnover With Tachycardia-Induced Cardiomyopathy

Elizabeth H. Stephens, BS; Tomasz A. Timek, MD; George T. Daughters, MD; Joyce J. Kuo, BS; Aaron M. Patton, BS; L. Scott Baggett, PhD; Neil B. Ingels, PhD; D. Craig Miller, MD; K. Jane Grande-Allen, PhD

From Department of Bioengineering (E.H.S., J.J.K., A.M.P., K.J.G.-A.) and Department of Statistics (L.S.B.), Rice University, Houston, Tex; Department of Cardiothoracic Surgery (T.A.T., G.T.D., N.B.I., D.C.M.), Stanford University School of Medicine, Stanford, Calif; Department of Cardiovascular Physiology and Biophysics (N.B.I., D.C.M.), Research Institute, Palo Alto Medical Foundation, Palo Alto, Calif.

Correspondence to K. Jane Grande-Allen, PhD, Bioengineering, Rice University, PO Box 1892-MS142, Houston, TX 77251-1892. E-mail grande{at}rice.edu

Background— Dilated cardiomyopathy (DCM) involves significant remodeling of the left ventricular–mitral valve (MV) complex, but little is known regarding the remodeling of the mitral leaflets. The aim of this study was to assess changes in matrix composition and turnover in MV leaflets with DCM.

Methods and Results— Radiopaque markers were implanted in 24 sheep to delineate the MV; 10 sheep underwent tachycardia-induced cardiomyopathy (TIC), whereas 14 sheep remained as controls. Biplane videofluoroscopy was performed before and after TIC. Immunohistochemistry was performed on leaflet cross-sections taken from the septal, lateral, anterior, and posterior commissures attachment segments. Staining intensity was quantified within each attachment segment and leaflet region (basal, mid-leaflet, and free edge). Mitral regurgitation increased from 0.2±0.4 before TIC to 2.2±0.9 after TIC (P<0.0002). TIC leaflets demonstrated significant remodeling compared to controls, including greater cell density and loss of leaflet layered structure (all P<0.05). Collagen and elastic fiber turnover was greater in TIC, as was the myofibroblast phenotype (all P<0.05). Compositional differences between TIC and control leaflets were heterogeneous by annular segment and leaflet region, and related to regional changes in leaflet segment length with TIC.

Conclusions— This study shows that the MV leaflets are significantly remodeled in DCM with changes in leaflet composition, structure, and valve cell phenotype. Understanding how alterations in leaflet mechanics, such as those induced by DCM, drive cell-mediated remodeling of the extracellular matrix will be important in developing future treatment strategies.

Key Words: cardiomyopathy • collagen • immunohistochemistry • metalloproteinases • mitral valve