3D characterization of ventricular myocardium in health, disease, and treatment




Li, David Shuen

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Cardiovascular diseases such as myocardial infarction and pulmonary arterial hypertension cause maladaptive remodeling of the heart, which drastically alters its function and progresses toward heart failure. Determining the mechanical drivers of remodeling, as well as therapeutic targets for its amelioration, is hampered by insufficient knowledge of the biomechanical environment of the myocardium at the tissue and cellular scales. Modeling of myocardial behavior has enabled the quantification of its mechanics and the in silico evaluation of cardiac disease therapies, but predictive models that account for full 3D mechanics are still lacking, facing hurdles in terms of (i) available experimental data from which to develop models, and (ii) understanding the complex mechanical behavior and interactions of constituents within the tissue. Clinical treatment strategies also depend on the critical link between organ-level function and the cellular-level microenvironment, necessitating multiscale modeling approaches in order to connect the two. To this end, the research presented in this dissertation focuses on both addressing current challenges in tissue-scale myocardial modeling as well as taking a first step in relating myocardial properties between the tissue and cellular scales. This work combines 3D modeling-driven optimal experimental design, multiaxial mechanical testing, high-resolution imaging, and finite element simulation. Through use of these integrated approaches, we achieve robust characterization of normal and diseased myocardium at the tissue scale within a full 3D framework. Next, we present a multiscale modeling platform for ventricular myocardium to elucidate cellular-scale stress transfer between myofibers and their surroundings, allowing for investigation of fiber-specific microstructural remodeling in response to disease. This research provides a foundation for improved models of myocardium capable of accurate prediction of therapeutic impacts on cell-, tissue-, and organ-level remodeling, ultimately aiding the development of patient-specific interventions and improvement of therapeutic outcomes.


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