Kara Garrott Dissertation Defense

Adapting Novel Techniques to Elevate Physiological Relevance to Study Heart Failure and Oxygenation
March 3, 2017

Department of Biomedical Engineering
Advisor: Dr. Matthew Kay

Date: Wednesday, March 29th, 1:00pm
Location: SEH Room 2000B

Cardiovascular disease is the leading cause of death in the United States with severe repercussions on society and individual lives. Despite recent research advancements, additional work is needed to more effectively diagnose and treat the wide range of cardiac afflictions. The isolated heart, developed by Oskar Langendorff in 1895, is a valuable tool to study cardiac function and disease. This preparation allows researchers to investigate whole organ function without confounding variables associated with in vivo methods, such as hormonal changes and spectral interference of blood. The isolated heart led to a greater understanding of cardiac electrophysiology and metabolism, which spurred the development of methods to diagnose and treat cardiovascular disease. Moving forward, ex vivo heart experiments must move closer to in vivo physiology in order to effectively recapitulate human conditions and reach translational potential.

The purpose of the studies presented in this dissertation is to implement and validate new techniques to study cardiac function and disease with more physiologically relevant conditions in the isolated heart model. The widespread effects of heart failure motivate the development of potential treatments. The research of this dissertation aims to reinstate the parasympathetic withdrawal that is characteristic of heart failure (HF) in a rat model by activation of parasympathetic oxytocin neurons. Application of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to increase cardiac parasympathetic tone in a rat model of HF reveals significant improvements in cardiac function and reductions in cardiac injury. Additionally, this dissertation more closely replicates in vivo physiology in fully contracting, working rabbit hearts to study electromechanical function and oxygen requirements. An innovative optical mapping technique to remove motion artifact in contracting hearts allows for sensitive measurements of electrical, mechanical, and metabolic function. Studying these parameters in tandem, rather than in isolation, allows for a more comprehensive understanding of cardiac function under conditions of hypoxia and increased work. These experiments also elucidate that KATP channels, ion channels that link the heart’s metabolic state to electrical function, are more readily activated in isolated heart preparations with greater work demands. The results of these studies and the previously established oxygen limitation due to crystalloid perfusate used in isolated heart experiments motivate the adaptation of a perfusate with 35% greater oxygen carrying capacity. Perfluorocarbon (PFC) solution binds oxygen with a greater affinity than crystalloid perfusate to bring studies of cardiac electrophysiology closer to physiological oxygenation conditions. The use of PFC solution in contracting heart optical mapping studies builds upon the developments previously established by this dissertation and moves closer towards in vivo physiology. PFC perfusate eliminated the oxygen limitation inherent to isolated heart preparations and provided enhanced protection against arrhythmogenesis. The clinical need for improved diagnosis and treatment of cardiovascular disease necessitates experimental research that mimics physiology with greater fidelity. This dissertation moves isolated heart experiments closer to in vivo physiology by using a new approach to reinstate parasympathetic tone in HF, revealing the role of KATP channels in contracting, working hearts, and vastly improving oxygenation in perfused heart studies.