Development of High Resolution Tools for Investigating Cardiac Arrhythmia Dynamics

Every year 300,000 Americans die due to sudden cardiac death. There are many pathologies, acquired and genetic, that can lead to sudden cardiac death. Regardless of the underlying pathology, death is frequently the result of ventricular tachycardia and/or fibrillation (VT/VF). Despite decades of research, the mechanisms of ventricular arrhythmia initiation and maintenance are still incompletely understood. A contributing factor to this lack of understanding is the limitations of the investigative tools used to study VT/VF. Arrhythmias are organ level phenomena that are governed by cellular interactions and as such, near cellular levels of resolution are needed to tease out their intricacies. They are also behaviors that are not limited by region, but dynamically affect the entirety of the heart. For these reasons, high-resolution methodologies capable of measuring electrophysiology of the whole entirety of the ventricles will play an important role in gaining a complete understanding of the principles that govern ventricular arrhythmia dynamics. They will also be essential in the development of novel therapies for arrhythmia management. In this dissertation, I first present the validation and characterization of a novel capacitive electrode design that overcomes the key limitations faced by modern implantable cardiac devices. I then outline the construction, methodologies, and open-source tools of an improved optical panoramic mapping system for small mammalian cardiac electrophysiology studies. I conclude with a small mammal study of the relationship between action potential duration restitution dynamics and the mechanisms of maintenance in ventricular arrhythmias

RHYTHM: An Open Source Imaging Toolkit for Cardiac Panoramic Optical Mapping

Fluorescence optical imaging techniques have revolutionized the field of cardiac electrophysiology and advanced our understanding of complex electrical activities such as arrhythmias. However, traditional monocular optical mapping systems, despite having high spatial resolution, are restricted to a two-dimensional (2D) field of view. Consequently, tracking complex three-dimensional (3D) electrical waves such as during ventricular fibrillation is challenging as the waves rapidly move in and out of the field of view. This problem has been solved by panoramic imaging which uses multiple cameras to measure the electrical activity from the entire epicardial surface. However, the diverse engineering skill set and substantial resource cost required to design and implement this solution have made it largely inaccessible to the biomedical research community at large. To address this barrier to entry, we present an open source toolkit for building panoramic optical mapping systems which includes the 3D printing of perfusion and imaging hardware, as well as software for data processing and analysis. In this paper, we describe the toolkit and demonstrate it on different mammalian hearts: mouse, rat, and rabbit

Optical mapping of successful and failed defibrillation

This chapter summarizes the current understanding of fibrillation and defibrillation mechanisms, and also explores one of the leading hypotheses of defibrillation, the virtual electrode polarization (VEP) hypothesis. The VEP hypothesis of defibrillation presents the most comprehensive explanation of defibrillation. It is based on solid experimental evidence and theoretical foundation. The chapter explores the VEP mechanism in more detail, especially in the context of successful and failed defibrillation mechanisms using optical mapping technology. The virtual electrode hypothesis of defibrillation, along with optical mapping techniques has made great strides toward explaining many experimentally and clinically observed phenomena, with implications for safe and efficient defibrillation. However, clinical advances are still to be gained from this knowledge. The authors believe further improvement of the VEP hypothesis of defibrillation may result in development of damage- and pain-free, effective and safe therapy that could realistically be translated to humans

Specialized impulse conduction pathway in the alligator heart

Mammals and birds have a specialized cardiac atrioventricular conduction system enabling rapid activation of both ventricles. This system may have evolved together with high heart rates to support their endothermic state (warm-bloodedness) and is seemingly lacking in ectothermic vertebrates from which first mammals then birds independently evolved. Here, we studied the conduction system in crocodiles (Alligator mississippiensis), the only ectothermic vertebrates with a full ventricular septum. We identified homologues of mammalian conduction system markers (Tbx3-Tbx5, Scn5a, Gja5, Nppa-Nppb) and show the presence of a functional atrioventricular bundle. The ventricular Purkinje network, however, was absent and slow ventricular conduction relied on trabecular myocardium, as it does in other ectothermic vertebrates. We propose the evolution of the atrioventricular bundle followed full ventricular septum formation prior to the development of high heart rates and endothermy. In contrast, the evolution of the ventricular Purkinje network is strongly associated with high heart rates and endothermy

Capacitively coupled arrays of multiplexed flexible silicon transistors for long-term cardiac electrophysiology

Advanced capabilities in electrical recording are essential for the treatment of heart-rhythm diseases. The most advanced technologies use flexible integrated electronics; however, the penetration of biological fluids into the underlying electronics and any ensuing electrochemical reactions pose significant safety risks. Here, we show that an ultrathin, leakage-free, biocompatible dielectric layer can completely seal an underlying layer of flexible electronics while allowing for electrophysiological measurements through capacitive coupling between tissue and the electronics, and thus without the need for direct metal contact. The resulting current-leakage levels and operational lifetimes are, respectively, four orders of magnitude smaller and between two and three orders of magnitude longer than those of any other flexible-electronics technology. Systematic electrophysiological studies with normal, paced and arrhythmic conditions in Langendorff hearts highlight the capabilities of the capacitive-coupling approach. Our technology provides a realistic pathway towards the broad applicability of biocompatible, flexible electronic implants