Fibrillatory activity in cardiac reaction-diffusion models with time-varying parameters

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CONTEXT***Atrial fibrillation (AF) is the most frequent arrhythmia and a major cause of stroke. My research program involves simulating these rhythm disorders in computer models of the atria to get insights into their mechanisms and investigate the factors promoting their occurrence. Cardiac electrical activity can be mathematically described by reaction-diffusion systems that integrate biological data from ion channel to organ anatomy. Some model parameters (e.g. ion channel conductances) may be regulated by external factors, e.g. by the autonomic nervous system through acetylcholine (ACh) release. We are going to study in a computational environment how time-dependent variation of parameters affects the vulnerability to atrial arrhythmias and the ensuing fibrillatory dynamics, using time-varying ACh action as a paradigm.******SPECIFIC AIMS ***We will investigate cholinergic AF, a form of AF associated with heterogeneity in ACh concentration in the cardiac tissue. This will provide us a physiologically-relevant framework to study the transient and long-term effects of a time-varying parameter (ACh concentration). Our short-term aims are:***(1) To develop a computer model of cholinergic AF. A 3D canine atrial model will be created. Algorithms will be developed to assign heterogeneous repolarization properties by automatically adjusting local ACh concentration. Temporal profiles of ACh variation (ACh release and degradation) will be designed and investigated.***(2) To simulate AF dynamics modulated by time-dependent ACh concentration. AF episodes will be induced in the model and the vulnerability to AF initiation will be assessed. The effect of different spatiotemporal profiles of ACh variation on AF dynamics will be studied: the position and size of ACh inhomogeneity, the peak value and time constants of ACh variation, and repolarization gradients will be varied.***(3) To monitor fibrillatory activity using a wavelength measure. Repolarization properties may change both in space and time and at a time scale shorter than a beat. These changes will be assessed by an instantaneous measure of the spatial extent of excitation waves (i.e. wavelength). For that purpose, a new computational technique will be developed, validated, and applied to cholinergic AF.******ORIGINALITY AND SIGNIFICANCE***Previous models had constant parameters. We are going to investigate how time-varying parameters may trigger a more complex AF dynamics or lead to AF self-termination. This may help explain the importance of autonomic activity in AF. Applications extend beyond cholinergic AF; external control of cell parameters may be achieved through light-sensitive channels introduced using optogenetics techniques. From a computational viewpoint, the new modeling tools developed will form the basis for further studies on heterogeneous arrhythmogenic substrates for AF.