Browsing by Subject "Remodeling"

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Remodeling of the mitral valve : an integrated approach for predicting long-term outcomes in disease and repair
(2019-12) Rego, Bruno Vale; Sacks, Michael S.; Baker, Aaron B; Yankeelov, Thomas E; Gorman, Robert C
Mitral regurgitation (MR) is the most prevalent valvular heart disease, afflicting 2.5% of the western-world population, and is becoming the next cardiac epidemic. MR is characterized by incomplete closure of the mitral valve (MV) caused by either primary (myxomatous degeneration and rheumatic fever) or secondary (ischemic left ventricular remodeling) etiologic factors. Ischemic MR (IMR) afflicts at least 300,000 Americans annually, an alarmingly high number that keeps rising as the population ages and grows. IMR is present in over 50% of patients with reduced left ventricular function induced by myocardial infarction. There are two major treatment strategies for IMR: valve replacement and valve repair. Although repair has long been embraced as the preferred treatment strategy, almost one third of patients experience recurrence of MR within a year of treatment. While new concepts and techniques for MV repair are continually emerging, these novel approaches must be developed with a profound understanding of MV tissue structure and mechanical behavior, which will depend on placing the MV in a larger context of overall left heart function. In addition, a detailed connection must be drawn between stress/strain at the tissue level and cellular deformation, as well as the remodeling pathways triggered via mechanotransduction in response to disease-induced alterations in geometric boundary conditions. In carrying out the research presented in this dissertation, I have aimed to address the questions of when, how, and to what extent the MV apparatus tissues physically remodel in the presence of both pathological (e.g., infarction) and non-pathological (e.g., pregnancy) perturbations to cardiac function. Additionally, I have built advanced computational finite element models to simulate the mechanical effects of disease on valvular function, and to relate disease progression to cellular and tissue-level remodeling phenomena. In parallel, I used state-of-the-art imaging and mechanical characterization tools to develop specialized structural constitutive models for valvular tissues that quantify the effects of microstructural and morphological heterogeneity on local tissue and cellular deformation, both of which play a large role in mediating valvular maintenance (in homeostasis) and remodeling (under non-homeostatic conditions such as disease). The ultimate goal of this work was to progress toward more generalized models of valvular remodeling following perturbations to cardiac function. This, in turn, will lay the groundwork for models that can better predict the outcomes of MV repair, and thus will facilitate the development of computational tools to design and optimize surgical repair strategies in silico