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

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.