Understanding the role of macrophages in the structural degeneration of bioprosthetic heart valve leaflets

ended

Heart valve disease is predicted to be the next cardiac epidemic. Valve prostheses used to treat this disease are comprised of biological tissue. However, these bioprosthetic leaflets degrade, limiting their long-term efficacy. Macrophages have been found within explanted leaflets and are key determinants of biocompatible outcome. However, their role in bioprosthetic leaflet remodelling is poorly understood. Males and females for unknown reasons are also predisposed to calcific and fibrotic leaflet degeneration, respectively. MACROVALVE’s goal is to elucidate the contribution of macrophages to the fibro-calcific remodelling of bioprosthetic leaflets. First, the applicant will apply histological, multi-omics and network analyses to constitute an integrated multi-omics map of human bioprosthetic leaflet degeneration. The differential pathogenesis between male and female disease will be determined. The results will also be compared against data for native aortic valve disease at different stages: early-disease, fibrotic and calcified. Electron microscopy will be used to identify extracellular vesicles. Secondly, the discrete response of sex-separated macrophages in the presence of hormonal milieu and physiological stimulation will be investigated. Ultimately, the innovative application of these techniques to unravel the innate immune response to bioprosthetic replacements will pave the way for novel therapeutics to prolong leaflet lifespan. The project is in line with the Horizon 2020 focus area Health, Demographic Change and Wellbeing. The candidate will spend the first two years of this fellowship training in multi-omics and network analyses at Brigham and Women’s Hospital in the United States. She will transfer these skills to Ireland during the return phase and increase Europe’s reputation as a location of cutting-edge research. Through this fellowship, the applicant will reach a position of professional maturity required for success in her future career.