Abstract
Early afterdepolarizations (EADs) are pathological voltage oscillations during the repolarization phase of cardiac action potentials. They are considered as potential precursors to cardiac arrhythmias and have recently gained much attention in the context of preclinical drug safety testing under the Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm. From the viewpoint of multiple time scales theory, the onset of EADs has previously been studied by means of mathematical action potential models with one slow ion channel gating variable. In this article, we for the first time associate EADs with mixed mode oscillations in dynamical systems with two slow gating variables and present a folded node singularity of the slow flow as a novel mechanism for EADs genesis. We derive regions of the pharmacology parameter space in which EADs occur using both the folded node analysis and a full system bifurcation analysis, and we suggest the normal distance to the boundary of the EADs region as a mechanism-based risk metric to computationally estimate a drug’s proarrhythmic liability.
Highlights
Afterdepolarizations (EADs) are abnormal depolarizations during the repolarization phase of the cardiac action potential and may be caused by drugs, oxidative stress or ion channelopathies
We have studied Early afterdepolarizations (EADs) in cardiac action potentials from the mathematical view point of mixed mode oscillations with multiple time scales
While the standard fast-slow analysis based on a single slow variable failed to explain the appearance of EADs in a parsimonious action potential model, a (1, 2)-fast-slow analysis based on two slow variables revealed that EADs may be caused by a folded node singularity if combined with a suitable global return mechanism
Summary
Afterdepolarizations (EADs) are abnormal depolarizations during the repolarization phase of the cardiac action potential and may be caused by drugs, oxidative stress or ion channelopathies. EADs propensity, expressed in terms of the net charge carried by major ionic currents during an action potential, has been chosen as an in-silico biomarker [3] for TdP risk evaluation of drugs within the CiPA (Comprehensive in vitro Proarrhythmia Assay) initiative [4], [5], [6] to overhaul the current cardiac drug safety regulations. Computational models of cardiac cells [7] form the basis for the mathematical analysis of EADs. The most common approach is to numerically simulate single cell action potential models after on purpose or random model parameter variations such that EADs occur [8], [9], [3], [10], [11], [12]. Numerical simulation studies have been performed at the cardiac
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