Abstract 2571: Persistent Phenotypic Alterations in Myocardial Fibroblasts Isolated from Human Dilated Cardiomyopathy Increase Extracellular Matrix Production
Background: A structural underpinning in patients with dilated cardiomyopathy (DCM) is LV remodeling, characterized by functional and compositional changes in the myocardial matrix, which includes collagen deposition and activation of matrix metalloproteases (MMPs). While an important cell type in the regulation of the matrix is the myocardial fibroblast (MF), whether inherent changes in MF phenotype occur in human DCM has not been directly examined. This study tested the hypothesis that persistent phenotypic alterations occur in matrix synthetic and degradative pathways in DCM MFs.
Methods/Results: LV free wall biopsies obtained from normal patients (n = 6) undergoing coronary revascularization (LV ejection fraction >55%) and DCM patients (n = 10) undergoing transplantation (LV ejection fraction < 20%) were subjected to a selective outgrowth method to produce confluent MF cultures and passages 1– 6 were measured for: protein (3H-Leu incorporation) and collagen secretion (3H-Pro incorporation), and release of soluble MMP-2 and MMP-9 (zymography). Protein and collagen secretion were increased from normal values (13.3±4.2 fg 3H-Leu/hr and 3.3±1.7 fg 3H-Pro/hr, respectively) in DCM (Figure⇓). While MMP-9 was not detected in DCM or normal MFs, MMP-2 release was similar between the two groups.
Conclusions: The unique findings from this study were that a persistent and differential functional phenotype was obtained in DCM MF cultures, including abnormalities in matrix synthetic pathways. These new results demonstrate that a contributory cellular mechanism and potential cellular therapeutic target for the LV remodeling in DCM patients is the fibroblast.