Abstract 1158: Mitral Leaflet Remodeling: Response to Isolated Mitral Regurgitation

Abstract

Objectives: Chronic mitral regurgitation (MR) adversely remodels the left ventricle. Although leaflet integrity is important for mitral coaptation, its response to isolated MR remains unknown. In a chronic ovine model, we hypothesize that isolated MR also adversely remodels the mitral leaflet. Methods: 29 sheep were randomized to either control (CTRL, n=11) or experimental groups (HOLE, n=18). In HOLE, a 2.8 – 4.8mm diameter hole was punched in the middle scallop of the posterior mitral leaflet. MR grade was followed by echocardiography. At 12 weeks, immunohistochemistry (IHC) was performed on anterior and posterior mitral leaflet cross-sections to demonstrate active matrix remodeling, including markers for active collagen synthesis synthesis and cross-linking prolyl 4-hydroxylase (P4H), heat shock protein 47 (HSP47), and lysyl oxidase (LOX) and matrix metalloproteinases (MMPs 1, 2, 9, 13) largely responsible for matrix degradation implicated in valvular pathologies. The proteoglycans biglycan (BGN), decorin (DC), and versican (VC), the glycosaminoglycan hyaluronan (HA), as well as fibrillin (F), and collagen III (col 3), all of which regulate matrix organization, were also visualized using IHC. A semi-quantitative intensity and delineation grading scale (from 0 to 3) was used to quantify differences between the HOLE and CTRL leaflets. Results: At 12 weeks, MR grade was greater in HOLE v CTRL (0.4±0.4 v 3.0±0.8, p < 0.001). In HOLE, valve matrix remodeling reduced hole diameter (69.5%32±.8%, p<0.001). The overall intensity of P4H, MMP13, and HSP47 decreased (1.02 v 1.30, p<0.02) while BGN, DC, and HA staining delineation increased 34 fold around the hole compared to CTRL (1.22 v 0.36, p<0.01). In the anterior leaflet of HOLE, P4H, LOX, MMPs, F, col 3, and HA were increased (1.43 v 1.24), while VC, DC, and BGN were decreased (1.66 v 1.84) compared to CTRL (both p≤0.05). Conclusions: In HOLE, significant remodeling was evident in the posterior leaflet near the site of injury; moreover expression of matrix turnover markers increased in the anterior leaflet due to the chronic low pressure LV volume overload. This adverse remodeling in the anterior leaflet in response to MR may explain how “MR begets MR,” providing insight for reparative surgical techniques.