Death due to lethal cardiac arrhythmias is the leading cause of mortality in Western society. Many of the fundamental mechanisms underlying the onset of arrthythmias, their maintenance and termination, still remain poorly understood. The specialized conduction (or His-Purkinje) system is fundamental to ventricular electrophysiological function and is a key player in various cardiac diseases. In recent years, computational simulation has become an important tool in im- proving our understanding ofthese mechanisms. Current state-of-the-art computational ventric- ular electrophysiology models often do not feature a detailed representation of the specialized conduction system. Ventricular models that do incorporate the specialized conduction system often use a simplified anatomical description and are commonly based on the monodomain equations, rather than the more general bidomain equations. Thus, using computational simula- tion to investigate both normal physiological function of the specialized conduction system and pathologies in which it is involved presents difficulties. This thesis develops the techniques and tools required to model the specialized conduction sys- tem at the ventricular scale. We derive one-dimensional bidomain equations that model elec- trical propagation in the system by reducing the equations associated with a three-dimensional fibre. To complement the derived equations, we develop a numerical solution scheme for the model that is efficient enough to allow ventricular simulations. The one-dimensional bido- main model allows defibrillation studies to be performed with the specialized conduction sys- tem. Secondly, we investigate the imaging and mesh generation tools required to integrate an anatomically detailed mesh of the specialized conduction system into a current state-of-the-art ventricular mesh. Using these tools, a highly detailed rabbit-specific specialized conduction system anatomical model is developed. Simulations are performed that dem~strate the re- sponse of the specialized conduction system to defibrillation strength shocks and we compare activation sequences generated using the model to experimental recordings. Finally, we investi- gate variability in the anatomy of the system. The tools and ventricular model presented in this thesis fulfil an important role in allowing the study of the e1ectrophysiological function of the specialized conduction system at the ventricular scale.

With current needs to better understand the interaction between atrial tissue microstructure and atrial fibrillation dynamics, micrometer scale imaging with optical coherence tomography has significant potential to provide further insight on arrhythmia mechanisms and improve treatment guidance. However, optical coherence tomography imaging of cardiac tissue in humans is largely unexplored, and the ability of optical coherence tomography to identify the structural substrate of atrial fibrillation has not yet been investigated. Therefore, the objective of this thesis was to develop an optical coherence tomography imaging atlas of the human heart, study the utility of optical coherence tomography in providing useful features of human left atrial tissues, and develop a framework for optical coherence tomography-informed cardiac modeling that could be used to probe dynamics between electrophysiology and tissue structure. Human left atrial tissues were comprehensively imaged by optical coherence tomography for the first time, providing an imaging atlas that can guide identification of left atrial tissue features from optical coherence tomography imaging. Optical coherence tomography image features corresponding to myofiber and collagen fiber orientation, adipose tissue, endocardial thickness and composition, and venous media were established. Varying collagen fiber distributions in the myocardial sleeves were identified within the pulmonary veins. A scheme for mapping optical coherence tomography data of dissected left atrial tissues to a three-dimensional, anatomical model of the human left atrium was also developed, enabling the mapping of distributions of imaged adipose tissue and fiber orientation to the whole left atrial geometry. These results inform future applications of structural substrate mapping in the human left atrium using optical coherence tomography-integrated catheters, as well as potential directions of ex vivo optical coherence tomography atrial imaging studies. Additionally, we developed a workflow for creating optical mapping models of atrial tissue as informed by optical coherence tomography. Tissue geometry, fiber orientation, ablation lesion geometry, and heterogeneous tissue types were extracted from optical coherence tomography images and incorporated into tissue-specific meshes. Electrophysiological propagation was simulated and combined with photon scattering simulations to evaluate the influence of tissue-specific structure on electrical and optical mapping signals. Through tissue-specific modeling of myofiber orientation, ablation lesions, and heterogeneous tissue types, the influence of myofiber orientation on transmural activation, the relationship between fluorescent signals and lesion geometry, and the blurring of optical mapping signals in the presence of heterogeneous tissue types were investigated. By providing a comprehensive optical coherence tomography image database of the human left atrium and a workflow for developing optical coherence tomography-informed cardiac tissue models, this work establishes the foundation for utilizing optical coherence tomography to improve the structural substrate characterization of atrial fibrillation. Future developments include analysis of optical coherence tomography imaged tissue structure with respect to clinical presentation, development of automated processing to better leverage the large amount of imaging data, enhancements and validation of the modeling scheme, and in vivo evaluation of the left atrial structural substrate through optical coherence tomography-integrated catheters

The immune system plays critical roles in the human heart in health, injury, and disease. Of the major immune cell types that reside in the cellular landscape of the myocardium, macrophages are particularly prevalent. Macrophages are responsible for a wide range of biological processes, including immunosurveillance, maintaining cardiomyocyte homeostasis, and regulating electrical conduction of cardiomyocytes. Within certain pathophysiological contexts such as Myocardial Infarction, they also facilitate the initiation and resolution of inflammation, and regulate cardiac repair and remodeling, significantly affecting injury trajectory and outcome. In addition to these already intricate interactions, both the immune system and the cardiovascular system are known to display sex-specific disparities, particularly under pathophysiological conditions, which may have important ramifications for patient health. The complex interplay within the human cardiac immune system has become increasingly evident, and therefore, understanding the interactions along the immune-cardiac axis and how they may vary among patient populations is of great interest to the clinical and research communities. An opportunity to study these interactions is presented by leveraging recent advances in induced pluripotent stem cell technology to engineer iPSC-derived models, which enable patient-specific studies of immune-cardiac interactions in a highly controllable environment. In this dissertation, we engineer patient-specific iPSC-derived models for studying immune-cardiac interactions. In Chapters 1 and 2, we introduce the importance of engineered models for studying the functions of the human heart, review the current state of the field, and identify key ways in which these models can be advanced. In Chapter 3, we create an iPSC-derived engineered cardiac tissue model with a resident macrophage population and investigate its impact on the function of the model under healthy conditions. In Chapter 4, we illustrate the capacity of iPSC-derived models to be patient-specific by showing how iPSC-derived macrophages demonstrate sex-specific dimorphism that emerges in response to an inflammatory stimulus. Finally, in Chapter 5, we present the optimization of an engineered model of myocardial ischemia reperfusion injury, which can be applied in future studies to study immune-cardiac interactions in the context of injury. Collectively, this dissertation provides a set of engineered tools that can be leveraged for improved understanding of the relationship between the heart and the immune system.