Abstract 16611: Impact of Mechanical Unloading on Structural and Non-structural Components of the Extracellular Matrix in Patients With Dilated Cardiomyopathy

Abstract

Introduction: Extracellular matrix (ECM) is the non-cellular component of the myocardium and its remodeling in cardiomyopathy is a major contributor to disease outcomes. While the impact of left ventricular assist device (LVAD) on remodeling of fibrillar ECM has been studied, its effects on the non-fibrillar ECM and matricellular proteins within the ECM that can influence cardiac structure and function are unknown. Hypothesis: Mechanical unloading preserves the non-fibrillar ECM composition, thereby contributing to reversal of adverse myocardial remodeling. Methods: Hearts were obtained from heart failure patients with idiopathic dilated cardiomyopathy (DCM) with LVAD support (>3mths; LVAD), without LVAD (no-LVAD), and non-failing control hearts (NFC) (n=10/group). LV free wall were fixed or flash-frozen for molecular and IHC evaluations. Results: Assessment of fibrillar ECM showed greater total and insoluble collagen content in no-LVAD hearts, consistent with an increase in collagen type I mRNA, and collagen type I-to-type III ratio. Proteolytic activities (collagenase & gelatinase) were significantly higher in no-LVAD (by 45% and 40%) suggesting greater ECM turnover in these hearts. TIMP1 mRNA decreased in both DCM groups (by 60%), but its protein decreased only in no-LVAD hearts (by 30%). TIMP3 and TIMP4 mRNA (by 30% and 55%) and protein (by 60% and 55%) decreased in both LVAD and no-LVAD hearts. ADAM-TS2, the N-terminal endopeptidase for collagen, was markedly lower in no-LVAD, while LOX1, the cross-linking enzyme showed a small increase in no-LVAD hearts. Evaluation of the basement membrane revealed that laminin arrangements were dispersed in no-LVAD hearts. Integrin β1, a cardiomyocyte cell-surface receptor for laminin, was reduced in no-LVAD but preserved in LVAD hearts. Other basement membrane proteins (fibronectin-1, collagen IV) showed similar trends, whereas differences in matricellular proteins (osteopontin, SPARC) were less striking between LVAD and no-LVAD hearts. Conclusions: Mechanical unloading positively impacts multiple aspects of myocardial ECM, the fibrillar ECM network and the less explored basement membrane, although the matricellular proteins residing within the ECM seem to be less affected.