| Sudden cardiac death is the leading cause of death in the western world, often a result of ventricular arrhythmia. The mechanisms underlying these arrhythmias are unclear, although it is believed that spatial gradients in repolarization lead to a pro-arrhythmic substrate. Therefore, assessing cardiac repolarization is critical in diagnosing diseases and deciding on appropriate therapies. Recording transmembrane action potentials in a beating heart is technically challenging. Therefore, inhomogeneities are often assessed through extracellular recordings such as the contact, suction and KCl monophasic action potential (MAP) or surface electrogram. While these techniques have undergone experimental validation, their biophysical origin and fidelity in the presence of inhomogeneities have not been systematically studied. The aim of this dissertation is to study, via mathematical, numerical and experimental models, the available extracellular methods of detecting and quantifying cardiac repolarization gradients. An analytical solution is derived, validated and used to gain rapid insight into potentials arising from both uniform and non-uniform substrates. A novel experimental preparation is used to characterize the depolarization under a contact MAP electrode. These experimental data are used to construct a computer model of the mouse ventricular freewall in which the genesis of the contact MAP is elucidated. We further extend the computational and analytic models to elucidate the origin of the suction and KCl MAP techniques. The results show that a monophasic signal may be recorded by two different mechanisms depending on the location and polarity of the electrodes, the nature of the depolarization and the height of the bath. To determine the impact of multiple inhomogeneities, we developed a realistic model of the mouse ventricles. The results show that even in a complex substrate, the MAP technique is a reliable measure of repolarization. The electrogram, on the other hand, can detect, but not quantify, changes in repolarization. In conclusion, we validate and determine the fidelity of the MAP technique and surface electrogram in detecting and quantifying cardiac inhomogeneities in repolarization. These studies will aid in determining appropriate measures for diagnosing diseases and monitoring therapies. |
