Bioprosthetic heart valve degeneration: new insights into structural remodeling and calcification.

Bioprosthetic heart valves (BHVs) are widely used to treat aortic valve disease, and their demand is rising. However, BHV lifespan remains limited by degeneration, with patients often requiring surgical or transcatheter reintervention within a decade. BHVs lack intrinsic remodeling capabilities, and the mechanisms contributing to their failure remain poorly understood. In this review, we summarize current knowledge of BHV degeneration by integrating findings from native aortic valve disease with studies of explanted bioprosthetic valves. We discuss the structural hallmarks of degeneration, including collagen remodeling, calcification, and inflammatory cell accumulation, and examine evidence that circulating blood-derived factors infiltrate BHV tissue and contribute to degeneration progression. Particular emphasis is placed on macrophages, which are consistently identified in explanted BHVs and may promote extracellular matrix (ECM) degradation. We also highlight extracellular vesicles (EVs) as potential mediators of cardiovascular calcification and propose that macrophage-derived EVs may promote ECM remodeling beyond sites of direct cellular accumulation. In addition, we review experimental approaches, including histological imaging, in vitro cell culture models, and proteomic analyses, that may help define molecular pathways underlying degeneration. Together, we hypothesize a model of BHV degeneration driven by interactions among host immune cells, circulating factors, and bioprosthetic tissue. Improved understanding of these mechanisms may facilitate the development of therapeutic strategies to improve BHV durability and long-term clinical outcomes.