Controlling Arrhythmias Using Optogenetic Actuators in Computational Simulations

Abstract

This dissertation discusses the application of light-induced stimulation (optogenetics) in computational models of heart cells (cardiomyocytes), cardiac tissues, and heart chambers to control arrhythmia development. Chapter 1 presents an overview of cardiac anatomy, relevant physiology, and cardiac electrophysiology computational models. Chapter 2 provides a basic explanation of optogenetic actuators (opsins), covering past applications (both experimental and computational) in cardiac tissue at various scales. Chapter 3 examines the efficacy of expressing an anion-conducting opsin (GtACR1) to terminate atrial and ventricular arrhythmias in 3D patient-derived models. Additionally, a 2-state photocurrent model for GtACR1 is introduced. Chapter 4 studies the use of subthreshold optogenetic stimulation to up- and down-regulate early afterdepolarization propensity (cell-scale) and related premature ventricular complexes (organ-scale) in patient models. Chapter 5 evaluates the use of optogenetic stimulation to modulate spontaneous beating in pluripotent stem cell-derived cardiomyocytes (cell-scale) and graft-to-host excitation in 2D, histology-derived tissue models (tissue-scale). The work presented here demonstrates how optogenetic stimulation can be used to control the initiation and suppression of arrhythmias in computational models across a variety of arrhythmia-prone conditions.