A probabilistic modeling framework for the prediction of spontaneous premature beats and reentry initiation

Spontaneously occurring life-threatening reentrant arrhythmias result when a propagating premature beat encounters a region with significant dispersion of refractoriness. Although localized structural tissue heterogeneities and prescribed cell functional gradients have been incorporated into computational electrophysiologic models, a quantitative framework for the evolution from normal to abnormal behavior that occurs by disease is lacking.

The purpose of this study was to develop a probabilistic modeling framework representing the complex interplay of cell function and tissue structure in health and disease that predicts the emergence of premature beats and the initiation of reentry.

An action potential model of the rabbit was developed with data-driven uncertainty characterization as done previously. A novel tissue model using the discrete-cell monodomain equations was developed by implementing cellular uncertainty as a random spatial field.

Cellular action potentials exhibited a wide range of duration and even a variety of behaviors, with 67% exhibiting normal repolarization, 27% displaying early afterdepolarizations, and 6% showing repolarization failure. Nevertheless, simulations in tissue resulted in localized synchronized repolarization. Thus, cellular variability provided "tissue-level robustness," and premature beats and reentry induction were never observed even with abnormalities in cell function (I_Kr block) or tissue structure (increased tissue resistance). Alterations of both cell function and tissue structure were necessary for the generation of premature beats and arrhythmia initiation.

Once extended to whole hearts and validated for a specific context, this modeling framework provides a means to predict the probability of the initiation of life-threatening arrhythmias.