Valvular Heart Disease: Advances, Challenges and the Path to Lifetime Management

Valvular heart disease (VHD) remains a leading contributor to global cardiovascular morbidity and mortality. Advances in valve replacement techniques, including the rise of bioprosthetic heart valves (BHVs), have improved outcomes for patients with severe VHD. Despite their hemodynamic benefits and the avoidance of lifelong anticoagulation therapy, BHVs face durability challenges due to structural valve degeneration (SVD). Looking ahead, the VHD population of the next decade is expected to comprise predominantly older individuals with histories of prior valvular interventions, placing them at high risk for additional surgical procedures. Addressing this evolving demographic will require major advancements in VHD management, including the development of effective transcatheter solutions and more durable bioprostheses to enable sustainable lifetime management of the disease. The first section of the thesis examines advancements in transcatheter mitral valve repair (TMVr) technologies, highlighting innovative designs that address the anatomical complexity of mitral regurgitation. It introduces a novel transcatheter device concept integrating direct annuloplasty and leaflet stabilization. The second section of the manuscript explores the evolving understanding of SVD mechanisms, emphasizing the role of immune-mediated processes and bioprosthetic antigenicity. The experimental study quantifies αGal epitopes—a major xenoantigen associated with immune responses and calcification—across various BHV models. Findings indicate significant residual immunogenicity in commercial BHVs, particularly porcine-derived valves, with αGal levels nearly twice as high as those in bovine pericardial valves. A polyphenol-based treatment demonstrated a 99% reduction in αGal epitope exposure, suggesting a promising approach for mitigating immune-driven SVD. Long-term in vitro studies further revealed that glutaraldehyde (GA), the primary crosslinking agent used in BHVs, undergoes depolymerization over time, leading to the progressive unmasking of antigens and sustained immune activation. This work underscores the need for a multidisciplinary approach to developing durable, biocompatible heart valve solutions. It addresses both immunological challenges and the structural demands of modern valve therapies. These findings pave the way for next-generation bioprostheses and transcatheter devices, advancing the goal of sustainable lifetime management for VHD patients.