Understanding the complex, self-organized electrical wave pattern underlying life-threatening car-diac arrhythmias remains a major scientific challenge, see section 1.3.2. The development of high-resolution fluorescence imaging of electrical activity on the surface of the heart has greatly improved the understanding of cardiac arrhythmias.128, 129, 153, 163 Despite this significant progress, fluorescence imaging does not permit the acquisition of information on electrical activity frominsidethe cardiac muscle, due to the low penetration depths of light in cardiac tissue. It is generally agreed that cardiac arrhythmia is an intrinisically three-dimensional phenomenon. Accordingly, the lack of appropriate three-dimensional imaging techniques imposes a substantial, impeding limitation.
This thesis aims to overcome this limitation of existing cardiac imaging techniques. Using high-resolution tomographic ultrasound to capture the mechanical deformation of the heart, this thesis explores novel approaches to visualize complex wave activity inside the cardiac muscle and investi-gates the relationship between the spatial-temporal dynamics of contractile and electrical activity.
The approach presented in this thesis is based on the assumption that the elasto-mechanical behav-ior of the deforming cardiac muscle reflects characteristic dynamical properties of the corresponding electrical wave pattern that causes the heart to deform. It is therefore expected that imaging of the mechanical deformations inside the heart’s wall during fibrillatory contractile activity would provide insight into the spatial-temporal self-organization during cardiac fibrillation corresponding to the in-tramural electrical wave patterns. The approach exploits the cardiac excitation-contraction coupling mechanism, which regulates the coupling of electrical and mechanical activity of the heart on the cel-lular level, and depends on its potential manifestation in closely coupled electromechanical activity
Chapter 1. Introduction
on the tissue level. It is proposed here that electromechanical activity in the heart is a closely coupled entity that retains a wave-like character with electrical waves causing a wave-like spread of mechan-ical activation, which subsequently allows the inverse imaging of electrmechan-ical activity from mechanmechan-ical deformation of the heart.
The main objective of this thesis is to provide a proof-of-concept of the possibility to perform inverse imaging of electrical activity from mechanical deformation and to demonstrate the feasibility of this approach to visualize transientintramuralwave patterns that underlie cardiac tachyarrhythmias.
This thesis combines experimental as well as computational work to investigate the electromechani-cal activity of the heart during cardiac tachyarrhythmias and explores ways to identify the electrielectromechani-cal activity from the structure of the mechanical activity.
The experimental work involves:
• study of ventricular fibrillation in intact, isolated rabbit hearts using high-speed optical fluores-cence and ultrasound imaging simultaneously, in order to acquire action potential and calcium transient wave patterns on the surface of the heart, as well as the elasto-mechanical activity on both the surface and inside the heart walls
• design and testing of possible experimental imaging setups and imaging configurations to be able to perform imaging as described above
• establishing that ultrasound imaging provides the desired imaging performance, such as speeds and spatial resolutions, that are necessary to resolve transient fibrillatory activity, as well as ensuring that it provides the capability of producing movie data of deforming cardiac tissue that can be used to extract the time-varying rapidly changing elastic deformation patterns
• analysis of electrical and mechanical wave patterns, comparing the patterns to each other to identify similar features between the two patterns that allow the association of the behavior of the elastic activity with particular behaviors of the electrical pattern
• identification of equipment and imaging technology, which is pertinent to the task of imaging electromechanical wave activity
The computational work involves:
• development of post-processing procedures that are necessary to be able to conduct the mea-surements, for instance the tracking of the cardiac deformations or the extraction of fluores-cence from moving cardiac substrates
• development of a computational model, consisting of a multi-physical description of electrical impulse propagation and accordingly contracting and deforming soft tissue, that allows the investigation of coupled electromechanical wave activity in cardiac muscle tissuein-silico
• development of computational procedures, with which the simulation data can be analyzed and visualized
Here, thein-silicostudies aim at establishing fundamental understanding of coupled electromechan-ical wave activity inside cardiac muscle tissue and, in particular, providing insight into the spatial-temporal patterns that are produced by the activity. Results are to guide the planning of experiments
with real cardiac tissue preparations, as well as enable interpretation of the measurements.
This thesis is organized as follows: chapters 5 and 6 present the main findings and results. Chapter 5 presents thein-silicostudies and chapter 6 presents the experimental results. Generally, results are presented in chapters 4, 5 and 6, where chapter 4 describes the work of the implementation of the computational model developed and used in this thesis for thein-silicostudies. Chapter 2 provides an introduction to the mathematical backgrounds. Chapter 3 contains an extensive literature review of imaging techniques, which were found to be pertinent for this study, but also presents original imag-ing data of cardiac tissue preparations obtained with different imagimag-ing techniques. The last chapter contains a summary of the results, conclusions and recommendations for further study. Each results chapter contains further literature references, description of the used methodolgy as well as a detailed documentation of experimental materials and methods.
Chapter 2. Mathematical Modeling of Cardiac Tissue