Arrhythmogenic effects of ultra-long and bistable cardiac action potentials.

Stewart Heitmann,Jamie I. Vandenberg,Anton Shpak,Adam P. Hill,Jeffrey J. Saucerman

doi:10.1371/journal.pcbi.1008683

Stewart Heitmann, Jamie I. Vandenberg + Show 3 more

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https://doi.org/10.1371/journal.pcbi.1008683

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Abstract

Contemporary accounts of the initiation of cardiac arrhythmias typically rely on after-depolarizations as the trigger for reentrant activity. The after-depolarizations are usually triggered by calcium entry or spontaneous release within the cells of the myocardium or the conduction system. Here we propose an alternative mechanism whereby arrhythmias are triggered autonomously by cardiac cells that fail to repolarize after a normal heartbeat. We investigated the proposal by representing the heart as an excitable medium of FitzHugh-Nagumo cells where a proportion of cells were capable of remaining depolarized indefinitely. As such, those cells exhibit bistable membrane dynamics. We found that heterogeneous media can tolerate a surprisingly large number of bistable cells and still support normal rhythmic activity. Yet there is a critical limit beyond which the medium is persistently arrhythmogenic. Numerical analysis revealed that the critical threshold for arrhythmogenesis depends on both the strength of the coupling between cells and the extent to which the abnormal cells resist repolarization. Moreover, arrhythmogenesis was found to emerge preferentially at tissue boundaries where cells naturally have fewer neighbors to influence their behavior. These findings may explain why atrial fibrillation typically originates from tissue boundaries such as the cuff of the pulmonary vein.

Highlights

Cardiac arrhythmias, which impair the heart’s ability to pump blood, are a major cause of morbidity [1] and mortality [2]
We propose an alternative mechanism whereby arrhythmias are initiated by cardiac cells that fail to repolarize of their own accord but still operate normally when embedded in functional heart tissue
We find that such cells can act as focal ectopic sources under appropriate conditions of inter-cellular coupling. Those cells are more prone to initiating arrhythmia when they are located on natural tissue boundaries

Summary

Introduction

Cardiac arrhythmias, which impair the heart’s ability to pump blood, are a major cause of morbidity [1] and mortality [2]. Arrhythmias are sustained by re-entrant rotors of electrical activity in the myocardium [3,4,5,6]. Contemporary theories of the genesis of arrhythmias are grounded in the concept of a trigger and a substrate [7]. The trigger for an arrhythmia is often attributed to spontaneous ectopic activity, such as early after-depolarizations (EADs) or delayed after-depolarizations (DADs), in one or more cardiomyocytes. Whereas the substrate refers to a state of the myocardium which is susceptible to initiating and supporting reentry. At least three factors can contribute to making the myocardium more vulnerable to initiating an arrhythmia. Heterogeneity in the refractoriness of cardiac cells, which is associated with arrhythmias in long QT syndrome [7] and is thought to predispose the tissue to uni-directional block [9, 10]

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