Mechanoregulation of endocardial to mesenchymal transformation and subsequent remodeling during heart valve development

Abstract

Nearly 300,000 heart valve (HV) replacement surgeries are performed annually, including both pediatric patients with valvular defects and elderly patients suffering from degenerative or calcific valve diseases. Worldwide, the incidence of congenital heart defects is ~1% of live births, and 1 in 4 of these require valve replacement surgery. Currently, the clinical available prostheses are classified as mechanical or bioprosthetic and present significant disadvantages for both young and old patient populations. For mechanical valves, typically comprised of Teflon- or silicone-based polymers and metals, the risk of thrombosis formation requires patients to remain on anticoagulant therapy. Bioprosthetic valves of either bovine or porcine origin introduce increased risk of calcific lesion formation after implantation. All prostheses have life spans of 10-20 years, which can necessitate multiple reoperations in the pediatric patient population who will also require larger HV replacements as they grow. The next generation of HV prosthetics needs to be viable, capable of actively responding to a patient’s needs to grow and remodel. To accomplish this, tissue engineered HVs (TEHVs) are moving towards natural polymer based scaffolds with cell-directive cues. However, to better develop these systems we will need to elucidate important biomechanical properties of HVs. By enhancing our understanding of mechanical factors essential in the formation and development of native HV leaflets, we can design improved viable TEHV scaffolds. The overall goal of this research is to elucidate the interactions between biomechanics and valvular cell processes crucial in HV leaflet development and remodeling. We are also interested in refining an in vitro model for epithelial to mesenchymal transformation (EMT), a critical initial step in the formation of HVs, that allows for interrogation of relevant biomechanical factors. We believe these studies provide novel insight into the relationship between mechanoregulation of EMT and HV tissue biomechanics.