Computational modelling and uncertainty quantification of blood flow in the coronary arteries
Keywords: Mechanical Engineering.

Atherosclerotic coronary artery disease continues to negatively impact the lives of millions worldwide. Computational fluid dynamics modeling of coronary blood flow has the potential to help improve clinical outcomes and aid in treatment planning. Significant advancements in coronary blood flow modeling in recent years have opened a wide range of applications such as assessing risk for disease progression or providing a platform for virtual surgery and treatment planning. To encourage the growth of this field and promote adoption of computational results in the clinic, it is crucial that these tools be made as automated as possible so they can be applied to large patient cohorts. In addition, the variability of computational results with respect to uncertainties in the inputs and model must be better understood and systematically quantified. Addressing these concerns is the subject of this thesis. In the first part, a framework for automatically tuning the lumped parameter boundary conditions in simulations of coronary blood flow is developed and demonstrated. Specifying boundary conditions in complex computational models is not a trivial task, especially when the dimensionality of the input space is high and multiple constraints on the outputs need to be satisfied simultaneously. Specifically in the context of patient-specific coronary simulations, clinical data such as the blood pressure, cardiac output, and coronary flow waveforms must be simultaneously satisfied with a large set of input parameters that include lumped resistances, capacitances, and heart model parameters. A typical user can eventually gain expertise to modify the input parameters to satisfy targets, but this manual tuning is time-consuming and not easily reproduced. We thus formulate the automated tuning process as a Bayesian inverse problem in which the model parameters are treated as random variables, and optimal parameters are determined by finding the maximum of the posterior distribution of input parameters. We also perform sensitivity analysis on the input parameters to determine a subset of thirteen parameters that most influence the clinical targets. In the second part, we perform uncertainty quantification on patient-specific simulations of coronary artery bypass graft hemodynamics. Vein graft failure in patients with coronary bypass continues to be a major clinical issue with relatively little knowledge about the mechanisms for failure. Simulations have shown that predicted quantities such as wall shear stress or wall strain can be useful in predicting vein graft failure, but adoption of such results in clinical practice is hindered due to the fact simulations can only produce deterministic results with no range of confidence. Uncertainty quantification provides a framework for quantifying the uncertainty in computational results, and we applied it to assess the variability in computed predictions of time-average wall shear stress and wall strain under uncertainty in the lumped parameter boundary conditions and vessel wall material properties. To achieve this aim efficiently, we develop a novel submodeling strategy for reducing the computational cost of the analysis. We also, for the first time, consider spatial variability in the graft wall material properties by using a random field description. We finally propagate these uncertainties forward using a newly developed multi-resolution approach. The results show that the time-averaged wall shear stress is relatively well estimated with confidence intervals about 35\% of the mean value, but the wall strain exhibited significantly more variability due to the large uncertainty in the material properties. In the third part, we perform a comparison of methods for modeling wall deformability in vascular blood flow simulations. Though sometimes neglected, wall deformability can have significant impacts on the computational results, affecting predictions of wall shear stress and precluding calculation of stresses and strains in the vessel wall. There are several methods proposed in the literature for modeling wall deformability, two of the most popular being the Arbitrary Lagrangian Eularian (ALE) and Couple Momentum Methods (CMM). Although both methods capture the essential characteristics of wall deformability, they can produce different results and computational performance. This provides a rigorous comparison which will aid in the choice of deformable wall model. Additionally, we consider the concept of prestress. Because the geometry for a patient-specific simulation is extracted from medical image data of the \textit{in vivo} cardiovascular system, the vessel walls carry an internal stress which holds the geometry in equilibrium with hemodynamic pressures and viscous stresses. We implement prestress in both ALE and CMM contexts and confirm that it is necessary to avoid over-inflation of the anatomic domain. Although studied mostly within the context of coronary flow simulations, the methods and approaches outlined in this thesis are designed to be generally applicable across other domains in computational modeling, fluid dynamics, and biomechanics. Automated tuning is a general framework for assimilating multiple sources of target data to inform optimal input parameter values, and can broadly be applied in multiscale modeling. The methods for uncertainty quantification can be adapted to assess variability of simulations in other computational fluid mechanics and biomechanics contexts. The results from the wall deformability comparison can also be extended to apply to other contexts including other cardiovascular diseases, respiratory flow, and medical devices. In addition to providing insights into coronary flow simulations, this thesis aims to motivate the importance of tuning, uncertainty quantification, and model comparisons for other cardiovascular simulations and multiscale biological modeling more broadly.