Abstract 525: In vitro Reverse Remodeling After Mechanical Unloading With Engineered Heart Tissue

Abstract

LVADs serve as a bridge to transplantation for many dilated cardiomyopathy (DCM) patients with advanced heart failure. In rare cases, mechanical unloading can lead to reverse myocardial remodeling sufficient for the removal of LVAD. We recreated the first reverse remodeling process in vitro in order to examine the role of active actin-myosin contraction and fibroblasts in contributing to this recovery, and to test the efficacy of drugs commonly prescribed for concurrent use with LVAD implantation. Engineered heart tissue (EHT) were prepared from decellularized porcine ventricular scaffolds in a proof-of-concept animal model with neonatal rat cardiomyocytes and subsequently with human induced pluripotent stem cell-derived cardiomyocytes and adult human cardiac fibroblasts. Mechanical stretch and myosin inhibition were used to simulate the pathological remodeling of DCM. Preliminary animal data showed that our model was able to capture the key features of DCM and reverse remodeling process including improved slack length, tissue stiffness, and active kinetics following mechanical unloading. β-adrenergic receptor response, protein assay, immunohistochemistry, and genetic analysis are being carried out to comprehensively investigate reverse remodeling in this artificial human system. Additional drug studies aim to investigate how reverse remodeling is affected by concurrent administration of β 1 antagonists and β 2 agonists (typical drug regimen for heart failure) and may inform new potential treatment during mechanical unloading to promote beneficial reverse remodeling for patients.