Remodeling of Pulmonary Cardiovascular Networks in the Presence of Hypertension

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The research team will develop mathematical and computational models for the study of pulmonary hypertension. This is a rare but rapidly progressing cardiovascular disease with a high mortality rate. Pulmonary hypertension involves both elevated blood pressure and changes in vessel wall stiffness, and thickness within the pulmonary circulation. These issues worsen with the severity of the disease. Diagnostic disease categories are associated with different parts of the pulmonary circulation network, yet pinpointing locations where the disease initiates is challenging. Models will be developed in conjunction with the use of experimental data provided by collaborators. This data will be obtained from non-invasive imaging of vascular blood flow and vessel network structure, and from invasive measurements of blood pressure in pulmonary vessels in mice and humans obtained via catheterization. Effects of the heart chambers, large vessels, small vessel networks and their interactions will be captured based on modeling and methodological approaches from fluid mechanics, solid mechanics, network analysis, inverse problems and parameter estimation. The proposed pulmonary cardiovascular model has potential to be incorporated into diagnostic protocols predicting pressure using non-invasive measurements to reduce the number of the invasive follow-up procedures, and to serve as a vital component for identifying signatures associated with disease diagnostic categories and the degree of disease progression. The overall project also provides a variety of opportunities for integrated training of a postdoc, and graduate and undergraduate students, in data-driven biomedical research.System-level, one-dimensional mathematical and computational fluid dynamics models of the pulmonary circulation will be developed. These models will include the right ventricle, left atrium, the large and small pulmonary arteries and veins, and account for alterations in the system components due to pulmonary hypertension. A physiologically based arterial and venous wall model that accounts for collagen and elastin content and that can also capture remodeling of wall constituents in response to pulmonary hypertension will be designed. This model will be rooted in nonlinear elasticity theory and will yield a more robust pressure-area relation that can be integrated within the fluid dynamics model, and linearized to facilitate the transition from large to small vessels. A second physiologically based right ventricle model combining ideas from simple elastance functions and single-fiber models will also be provided. This model will enable prediction of elastance as a function of right ventricle thickness. The analysis will focus on the pulmonary circulation, but impacts on modeling systemic circulation in a comprehensive closed loop model will also be considered. The models developed in these two aims will be used to simulate and identify flow and pressure waveforms that predict features associated with disease progression and, via sensitivity analysis and parameter estimation, to render the model patient-specific. With these innovations it will be possible to use the one dimensional system level model combined with pulmonary arterial blood pressure from non-invasive measurements of flow to assess disease progression associated with pulmonary hypertension while also reducing the number of invasive measurements.