Characterization and modeling of the human left atrium using optical coherence tomography Theresa Huang Lye Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 2019 Theresa Huang Lye All Rights Reserved ABSTRACT Characterization and modeling of the human left atrium using optical coherence tomography Theresa Huang Lye 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. Table of Contents List of Abbreviations .................................................................................................................... vii List of Figures ................................................................................................................................ ix List of Tables ............................................................................................................................... xxi Acknowledgements ..................................................................................................................... xxii Chapter 1 Background and Significance......................................................................................... 1 1.1 Atrial Fibrillation................................................................................................................... 1 1.2 Radiofrequency Ablation ...................................................................................................... 2 1.2.1 Overview ........................................................................................................................ 2 1.2.2 Additional Ablation Strategies ....................................................................................... 4 1.2.3 Remaining Challenges in Radiofrequency Ablation ...................................................... 5 1.3 Cardiac Imaging and Modeling ............................................................................................. 6 1.3.1 Atria Imaging and Electrophysiological Models ............................................................ 6 1.3.2 Optical Mapping ............................................................................................................. 8 1.3.3 Remaining Challenges in Left Atrial Imaging and Modeling ........................................ 8 1.4 Optical Coherence Tomography ........................................................................................... 9 i 1.4.1 Time Domain Optical Coherence Tomography ........................................................... 10 1.4.2 Fourier Domain Optical Coherence Tomography ........................................................ 12 1.4.3 Optical Coherence Tomography Parameters ................................................................ 13 1.5 Cardiac Applications of Optical Coherence Tomography .................................................. 15 1.5.1 OCT Imaging of Cardiac Structure in Animal Models ................................................ 15 1.5.2 OCT Imaging for Radiofrequency Ablation Guidance ................................................ 16 1.5.3 OCT Imaging of the Human Heart ............................................................................... 17 1.6 Objectives ............................................................................................................................ 18 Chapter 2 Comprehensive Characterization of the Human Left Atrium with Optical Coherence Tomography .................................................................................................................................. 19 2.1 Introduction ......................................................................................................................... 19 2.1.1 Myofiber Orientation in the Left Atrium ...................................................................... 19 2.1.2 Fibrosis in the Left Atrium ........................................................................................... 20 2.1.3 Other Structural Substrates of Atrial Fibrillation ......................................................... 22 2.1.4 OCT Imaging of the Human Left Atrium and Objective ............................................. 24 2.2 Methods ............................................................................................................................... 24 2.2.1 Tissue Acquisition ........................................................................................................ 24 ii 2.2.2 Dissection Protocol ....................................................................................................... 26 2.2.3 Imaging Protocol .......................................................................................................... 27 2.2.4 Histology ...................................................................................................................... 28 2.2.5 Image Processing .......................................................................................................... 29 2.3 Results ................................................................................................................................. 36 2.3.1 Endocardium ................................................................................................................. 36 2.3.2 Adipose ......................................................................................................................... 37 2.3.3 Myofiber Orientation and Collagen fibers .................................................................... 41 2.3.4 Pulmonary Veins .......................................................................................................... 46 2.3.5 Interatrial Septum ......................................................................................................... 54 2.3.6 Ablation Lesions ........................................................................................................... 56 2.3.7 Whole Human Cardiac Atlas .......................................................................................