Date of Award
Spring 3-14-2024
Embargo Period
3-14-2029
Document Type
Dissertation - MUSC Only
Degree Name
Doctor of Philosophy (PhD)
Department
Cell Biology and Regenerative Medicine
Additional Department
Molecular and Cellular Biology and Pathobiology
College
College of Graduate Studies
First Advisor
Russell Norris
Second Advisor
Michael Yost
Third Advisor
Amy Bradshaw
Fourth Advisor
Carol Feghali-Bostick
Fifth Advisor
Jeffrey Jones
Abstract
Mitral Valve Prolapse (MVP) is a common heart valve condition characterized by superior displacement of one or both mitral valve leaflets during systole and often failure of leaflet coaptation. Although historically thought of as a benign condition, with secondary consequences thought to occur as a result of worsening mitral regurgitation (MR), recent studies have highlighted an association between MVP, regionalized myocardial fibrosis of the subvalvular myocardium, and potentially lethal ventricular tachyarrhythmias including ventricular tachycardia (VT) and ventricular fibrillation (VF). Often, patients who present with life-threatening arrhythmias have a phenotypically “moderate” regurgitation and are not surgical candidates; Yet, other clinically measurable variables suggest these patients present with a mechanically severe form of MVP, characterized by bi-leaflet involvement, abnormal myocardial and annular mechanics during systole, and mitral annular disjunction (MAD). Nonetheless, current AHA/ACC medical and surgical guidelines do not adequately risk stratify MVP patients based on the mechanical severity of their disease. Furthermore, the underlying mechano-molecular interactions that initiate and sustain fibrosis and arrhythmias in MVP are not well understood and represent an unmet clinical need for therapeutics which can slow or reverse mechanically-induced fibrosis. This dissertation reviews the macroscopic and microscopic anatomy of the mitral valve as well as what is known about the clinical causes and consequences of mitral valve prolapse, including ventricular arrhythmias. We further test the hypothesis that mitral valve prolapse induces regionalized left ventricular fibrosis by increasing mechanical stress on the subvalvular myocardium, which in turn activates fibrogenic pathways within cardiac fibroblasts. In aim 1, we demonstrate regionalized myocardial fibrosis occurs in human patients at the time of MV surgery with increases in CD206 expressing macrophages, and a-Smooth Muscle Actin expressing myofibroblasts in valve-linked myocardial regions. We additionally show that induction of MVP using a geneticallyaccurate mouse model of human non-syndromic MVP phenocopies the human findings and causes progressive myocardial fibrosis with time. In aim 2, we develop a non-genetic surgical model of MVP in a large animal which allows us to induce prolapse and the associated mechanical stress with a genetically normal myocardium and test the response of subvalvular myocardium to mechanical stress. We show that surgical induction of MVP causes regionalized fibrosis, consistent with a mechanism of regionalized fibrosis secondary to abnormal valve induced mechanical stress on the subvalvular myocardium. In aim 3, we apply mechanical stress in the form of stiffness to primary human cardiac fibroblasts and perform an integrative, multi- ‘omic’ profiling analysis in order to identify pathways which drive mechanical stress-induced fibrosis. We show that mechanical stress induces broad transcriptional and epigenetic changes consistent with upregulation of fibrogenic pathways. Our results identify the mechanosensitive gene MYH10, which encodes non-muscle myosin IIB, and demonstrate how transcription of MYH10 is epigenetically regulated by mechanical stress through an intronic repressor element which binds the transcription factor JUND. Finally, we highlight potential upstream signaling pathways which may regulate MYH10, including purinergic signaling by Connexin 43 hemichannels. Conclusions from this work are that regionalized fibrosis in MVP is progressive, occurs secondary to the valve defect, and is in part driven by pathways which may be targeted using pharmacotherapeutics. Our work further questions whether earlier surgical intervention in a subset of MVP patients may reduce the risk of lethal ventricular arrhythmias and be of therapeutic value.
Recommended Citation
Morningstar, Jordan, "A Mechano-Molecular Landscape Underlying Regionalized Left Ventricular Fibrosis in Mitral Valve Prolapse" (2024). MUSC Theses and Dissertations. 845.
https://medica-musc.researchcommons.org/theses/845
Rights
Copyright is held by the author. All rights reserved.