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

Transmural APD gradient synchronizes repolarization in the human left ventricular wall

The duration and morphology of the T wave predict risk for ventricular fibrillation. A transmural gradient in action potential duration (APD) in the ventricular wall has been suggested to underlie the T wave in humans. We hypothesize that the transmural gradient in APD compensates for the normal endocardium-to-epicardium activation sequence and synchronizes repolarization in the human ventricular wall

Transmural APD gradient synchronizes repolarization in the human left ventricular wall

Aims The duration and morphology of the T wave predict risk for ventricular fibrillation. A transmural gradient in action potential duration (APD) in the ventricular wall has been suggested to underlie the T wave in humans. We hypothesize that the transmural gradient in APD compensates for the normal endocardium-to-epicardium activation sequence and synchronizes repolarization in the human ventricular wall. Methods and results We made left ventricular wedge preparations from 10 human donor hearts and measured transmural activation and repolarization patterns by optical mapping, while simultaneously recording a pseudo-ECG. We also studied the relation between local timings of repolarization with the T wave in silico. During endocardial pacing (1 Hz), APD was longer at the subendocardium than at the subepicardium (360+17 vs. 317+ 20 ms, P, 0.05). The transmural activation time was 32+4 ms and resulted in final repolarization of the subepicardium at 349+ 18 ms. The overall transmural disper