Spatiotemporal Control Of Action Potential Duration Alternans In Ventricular Tissue
Cardiac electrical alternans, sometimes referred to as action potential duration (APD) alternans, is a beat-to-beat alternation in action potential waveform, which naturally occurs at sufficiently fast pacing rates. Its presence has been putatively linked to the onset of cardiac reentry, which is a precursor to ventricular fibrillation (VF). Because of the established link between APD alternans and the onset of VF, it may be beneficial to develop means to terminate and/or prevent alternans in cardiac tissue. Closed-loop feedback mechanisms aimed at controlling a dynamically stable period-2 rhythm (alternans) to an unstable period-1 rhythm (no alternans) using singlesite intervention from an external source may be one such option. Previous studies that have utilized this alternans control approach have shown that closed-loop alternans control techniques that apply a succession of externally-administered cycle perturbations at a single site provide limited spatially-extended alternans elimination in sufficiently large cardiac substrates. However, detailed investigations into the spatial dynamics of alternans control have been largely restricted to Purkinje fiber studies. A complete understanding of alternans control in the more clinically relevant ventricular tissue is needed if more advanced electrode-based intervention techniques are to be developed for cardiac alternans therapy. In this work, both mathematical modeling of simulated cardiac tissue and fluorescence imaging of right ventricular cardiac preparations were used to better understand the characteristics of alternans and alternans control in ventricular tissue. In the first part of this work, alternans and alternans control was simulated in one-dimensional cables using the Shiferaw-Sato-Karma (SSK) computational model. The model parameters were varied in order to simulate alternans and alternans control under several different mechanistic manifestations of alternans. Furthermore, the spatial extent of alternans control was systematically probed under varying cable lengths and basic cycle lengths (BCLs) in an attempt to quantify spatial alternans dynamics. In the second part of the study, alternans and alternans control experiments were performed using a custom-designed optical mapping system capable of highresolution imaging. In this way, the spatial efficacy of alternans control was quantified in an experimental setting, and furthermore, the observation and analysis of APD and repolarization dynamics were made possible. In the third part of the study, the effects of noise on alternans control were investigated using SSK implemented simulations of single cell and 1-D arrangements of ventricular tissue. The results of this study will aid in future alternans control experiments, which can occur in the presence of varying amounts of noise. This work represents the first attempts to directly investigate alternans and alternans control in ventricular tissue. Clinical realization of advanced electrodebased therapies for alternans and other related cardiac electrical abnormalities will benefit from the insights gained from this and future related studies.
alternans; cardiac arrhythmias; nonlinear dynamics
Gilmour Jr., Robert F; Victor, Jonathan David
Ph.D. of Biomedical Engineering
Doctor of Philosophy
dissertation or thesis