The role of tissue heterogeneities in myocardial excitation and propagatio

Despite major advances in knowledge of the genesis and termination of cardiac arrhythmias, both ventricular and supraventricular rhythm disturbances remain lethal pathologies endemic to industrialized nations. While the elucidation of arrhythmogenic mechanisms requires a full understanding of myocardial excitation and propagation, there exist essential unknowns in terms of the contribution of structural heterogeneities. To more fully characterize the influence of myocardial structure on cardiac excitation and propagation, the role of tissue architecture is investigated via computational modeling at both microstructural and macrostructural levels.;Chamber geometry and fiber direction lend significant macrostructural heterogeneity to the ventricles. However, the role of these heterogeneities during field stimulation in diastole had not been examined. Results reveal that ventricular geometry and fiber architecture play a critical role in determination of the location and size of shock-induced virtual anodes that lead to activation delay during the shock and subsequently affect postshock propagation during field stimulation in diastole.;At the microstructural level, the architectural and functional heterogeneity of cardiac fibrosis may provide a basis for conduction abnormalities, but the contribution of fibroblast membrane kinetics has remained unexplored in the context of the human atria, a region with a lower safety factor for repolarization.;Because such a study requires that repolarization processes of the human atrial myocyte be represented as accurately as possible, an updated mathematical model was developed. The reformulations are sufficiently extensive and insightful so as to demonstrate ionic mechanisms responsible for excitability and repolarization reserve in the human atrial myocyte, in addition to providing a useful computational tool. The results of the subsequent fibroblast-atrial myocyte electrotonic coupling simulations employing the updated ionic model reveal marked effects on resting membrane potential and action potential waveform of the myocyte: electrotonic coupling to fibroblasts can have significant effects on myocyte excitability.;These studies have contributed to the body of knowledge regarding the role of myocardial micro- and macrostructural heterogeneities in cardiac excitation and propagation. Future integrative models incorporating multiple levels of tissue architecture may further assist in the achievement of a global understanding of the ways in which structural and functional organization of the myocardium influences arrhythmogenesis.