Abstract 2293: Significant Changes in Mitral Valve Leaflet Matrix Composition and Turnover with Dilated Cardiomyopathy
Objectives: 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 the MV leaflets with DCM.
Methods: Radiopaque markers were implanted in 24 sheep to delineate the MV; 10 sheep underwent tachycardia induced cardiomyopathy (TIC) while 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, and anterior and posterior commissures (CA, CP) attachment segments. Staining intensity was quantified within each attachment segment, leaflet region (basal, mid-leaflet, and free edge), and histological layer using ImageJ Pro software.
Results: MR increased from 0.3 ± 2 before TIC to 2.2 ± 0.9 after TIC (p<0.0001). TIC leaflets showed significant remodeling with increased leaflet length (p=0.044) and increased cell density in the basal and mid-leaflet compared to controls (p<0.05). Consistent with increased collagen turnover in TIC, matrix metalloprotease (MMP)-13 expression in the CA and lateral mid-leaflet (both p<0.025), MMP9 in the lateral mid-leaflet (p=0.031), collagen I intensity in the lateral basal leaflet (p=0.005) and all regions of the CA (all p<0.02), and collagen III in the lateral basal leaflet (p=0.015) and CA fibrosa layer (p=0.007) were all greater in TIC compared to controls. Furthermore, valve cell activation was increased in TIC leaflets as evidenced by greater smooth muscle alpha actin in the CA, CP, and lateral mid-leaflet (all p<0.02) and greater non-muscle myosin in the lateral basal leaflet and CP mid-leaflet (both p<0.05) of TIC compared to controls. Elastin was greater in TIC septal mid-leaflet (p<0.001) and TIC atrialis and fibrosa layers across all segments (p<0.001). However, in the TIC septal leaflet, Col III was less than controls (all regions p<0.03).
Conclusions: This study shows that the MV leaflets are significantly remodeled in DCM with changes in leaflet composition, structure, dimensions, and valve cell phenotype. This remodeling could be an important factor in the MR associated with DCM.