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(Circulation. 2008;118:S243-S249.)
© 2008 American Heart Association, Inc.

Surgery for Valvular Heart Disease

The Effects of Mitral Regurgitation Alone Are Sufficient for Leaflet Remodeling

Elizabeth H. Stephens, BS; Tom C. Nguyen, MD; Akinobu Itoh, MD; Neil B. Ingels, Jr, PhD; D. Craig Miller, MD; K. Jane Grande-Allen, PhD

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

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—— Although chronic mitral regurgitation results in adverse left ventricular remodeling, its effect on the mitral valve leaflets per se is unknown. In a chronic ovine model, we tested whether isolated mitral regurgitation alone was sufficient to remodel the anterior mitral leaflet.

Methods and Results— Twenty-nine sheep were randomized to either control (CTRL, n=11) or experimental (HOLE, n=18) groups. In HOLE, a 2.8- to 4.8-mm diameter hole was punched in the middle scallop of the posterior mitral leaflet to create "pure" mitral regurgitation. At 12 weeks, the anterior mitral leaflet was analyzed immunohistochemically to assess markers of collagen and elastin synthesis as well as matrix metalloproteinases and proteoglycans. A semiquantitative grading scale for characteristics such as intensity and delineation of stain between layers was used to quantify differences between HOLE and CTRL specimens across the heterogeneous leaflet structure. At 12 weeks, mitral regurgitation grade was greater in HOLE versus CTRL (3.0±0.8 versus 0.4±0.4, P<0.001). In HOLE anterior mitral leaflet, saffron-staining collagen (Movat) decreased, consistent with an increase in matrix metalloproteases throughout the leaflet. Type III collagen expression was increased in the midleaflet and free edge and expression of prolyl-4-hydroxylase (indicating collagen synthesis) was increased in the spongiosa layer. The proteoglycan decorin, also involved in collagen fibrillogenesis, was increased compared with CTRL (all P0.05).

Conclusions— In HOLE anterior mitral leaflet, the increased expression of proteins related to collagen synthesis and matrix degradation suggests active matrix turnover. These are the first observations showing that regurgitation alone can stimulate mitral leaflet remodeling. Such leaflet remodeling needs to be considered in reparative surgical techniques.

Key Words: collagen • immunohistochemistry • regurgitation • remodeling • valves

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				E. H. Stephens, T. A. Timek, G. T. Daughters, J. J. Kuo, A. M. Patton, L. S. Baggett, N. B. Ingels, D. C. Miller, and K. J. Grande-Allen Significant Changes in Mitral Valve Leaflet Matrix Composition and Turnover With Tachycardia-Induced Cardiomyopathy Circulation, September 15, 2009; 120(11_suppl_1): S112 - S119. [Abstract] [Full Text] [PDF]