SUMMARY Bioprosthetic heart valves (BHV), made from glutaraldehyde-fixed xenografts, are widely used for surgical (SAVR) and transcatheter valve interventions (TAVR), but suffer from limited durability due to Structural Valve Degeneration (SVD). Advances in BHV device engineering and delivery have created the possibility to provide state-of-the-art care to heart valve disease patients that were once deemed inoperable due to their risk score and advanced co-morbidities. However, the same class of devices is offered to all patients, irrespectively of their co-morbidities and susceptibility to structural valve degeneration. Metabolic syndrome (MetS) is a common comorbidity in patients who require BHV and is a known risk factor for cardiovascular diseases. Our published and preliminary results show the enhanced susceptibility of bio-implantable materials to oxidation, glycation, pro- calcific proteins, and crosslinkers in patients with Metabolic Syndrome or rodent model of MetS, using Zucker Diabetic Fatty (ZDF, Obese fa/fa). We have also shown that poly-2-methyl-2-oxazoline (POZ) functionalization of clinically graded BHVs and bovine pericardium mitigates SVD by reducing protein absorption, decreasing glycation, and oxidation products accumulation, and enhancing thromboresistance. Notably, POZ functionalization reduces calcification using human serum-incubation assays and subcutaneous implants in ZDF rats. In MetS patients, both surgical (SAVR) and percutaneous (TAVR) approaches are valid treatment options, although some recent studies raise the possibility that, in the long term SAVR could exhibit higher survival rates. Finally, given their conditions, MetS patients are often pharmacologically treated to control hyperglycemia and high-density lipoprotein cholesterol. Therefore, SVD - in the clinical setting of Metabolic Syndrome - is driven by three main factors: a) the biochemical profile of the patients, b) device selection and the susceptibility of the implanted material to degradation, and c) the pharmacological treatments that MetS patients are receiving. This application will address these three aspects and test the hypothesis that a combination of POZ-modified surgical or transcatheter bioprosthetic valve and pharmacological management of MetS is needed to mitigate SVD and improve durability. Once completed, the expected outcomes are to identify the main driving factors responsible for the accelerated structural degeneration and calcification of implantable materials in patients with MetS.