STRUCTURO-MECHANICAL DEVELOPMENT OF THE MITRAL VALVE AND ITS CHORDAE TENDINEAE IN A FETAL BOVINE MODEL
Date
2024-12-15
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Abstract
Our lab discovered that maternal heart valves undergo adaptive remodeling during pregnancy, including increased leaflet area and more chordae tendineae attachments—a process seen only during fetal development. This thesis investigates fetal mitral valve development in a bovine model using a materials science approach. Chapter two highlights rapid chordae tendineae development in bovine mitral valves, achieving adult-like structure by term despite postpartum leaflet expansion. Chapters three and four propose the first comprehensive hypothesis of chordae formation to date using various imaging modalities and direct mechanical testing. We suggest that chordae initiation begins at the transition zone, where endothelial cells drive matrix remodeling using MMP-1 and 2 to create perforations, enabling the split of a single attachment into two. These findings offer insights into mitral valve development and may inform tissue-engineering innovations crucial for addressing the growing burden of heart valve disease.
Description
Our lab observed, for the first time, that the maternal heart valves undergo adaptive remodeling in response to volume overload in pregnancy. Distinct from pathological remodeling, this includes increasing leaflet area and number of chordae tendineae attachments. The only other time in life where an increase in chordal attachment number is observed is during fetal development. Inspired by adaptive pregnancy remodeling, this thesis explores the development of the fetal mitral valve in a bovine model using a materials science approach.
Chapter two describes the structural changes in the mitral valve anterior leaflet and chordae tendineae during fetal development in a large animal with a gestational period similar to humans. In contrast to small mammals, bovine mitral valve chordae tendineae rapidly develop, achieving adult-like architecture by term. These anatomical changes involve rapid accumulation and maturation of collagen in the chordae that outpaces the leaflet. In contrast, the leaflet led the chordae in the appearance of mature elastic fibers. Despite continued leaflet expansion postpartum, chordae attachments remain unchanged, suggesting fetal development drives chordae division mechanisms. The mitral valve components possess distinct developmental programming, despite the nearly continuous collagen fiber architecture between them.
Chapters three and four provide the first comprehensive hypothesis of chordae tendineae formation to date. Based on our observations from three imaging modalities (light microscopy, transmission electron microscopy, and micro computed tomography) we propose that chordae initiation occurs at the transition zone, a site of unique extracellular matrix organization with cell-lined perforations in the structure. Endothelial cell expression of MMP-1 and 2 will lead to local tissue degradation to create these perforations, possibly in response to leaflet thinning as it rapidly grows during development. These perforations will then split one attachment site on the ventricular face into two. This split will continue to propagate along the common trunk forming two branches as the chordae possess some cleavage plane that predisposes them for splitting. The energetic cost both to break apart collagen bundles and create new tissue area rapidly increases in the third trimester, suggesting that this splitting ability is reduced leading up to full term, supporting our previous results.
Altogether, this work has provided new insights into the formation of the mitral valve and associated chordae tendineae in a large mammalian model. These results have the potential to further tissue engineering designs of atrioventricular valves and to further elucidate the mechanisms of adaptive pregnancy remodeling. With the increasing prevalence of heart valve disease, innovations in treatment are urgently needed.
Keywords
Valvulogenesis, Cardiac Development, Collagen, Elastin, Mitral Valve, Chordae Tendineae, Anterior Leaflet