Abstract
Sudden cardiac death is often caused by cardiac arrhythmias. Recently, special attention has been given to a certain arrhythmogenic condition, the long-QT syndrome, which occurs as a result of genetic mutations or drug toxicity. The underlying mechanisms of arrhythmias, caused by the long-QT syndrome, are not fully understood. However, arrhythmias are often connected to special excitations of cardiac cells, called early afterdepolarizations (EADs), which are depolarizations during the repolarizing phase of the action potential. So far, EADs have been studied mainly in isolated cardiac cells. However, the question on how EADs at the single-cell level can result in fibrillation at the tissue level, especially in human cell models, has not been widely studied yet. In this paper, we study wave patterns that result from single-cell EAD dynamics in a mathematical model for human ventricular cardiac tissue. We induce EADs by modeling experimental conditions which have been shown to evoke EADs at a single-cell level: by an increase of L-type Ca currents and a decrease of the delayed rectifier potassium currents. We show that, at the tissue level and depending on these parameters, three types of abnormal wave patterns emerge. We classify them into two types of spiral fibrillation and one type of oscillatory dynamics. Moreover, we find that the emergent wave patterns can be driven by calcium or sodium currents and we find phase waves in the oscillatory excitation regime. From our simulations we predict that arrhythmias caused by EADs can occur during normal wave propagation and do not require tissue heterogeneities. Experimental verification of our results is possible for experiments at the cell-culture level, where EADs can be induced by an increase of the L-type calcium conductance and by the application of I blockers, and the properties of the emergent patterns can be studied by optical mapping of the voltage and calcium.
Highlights
The mechanical pumping of the heart is initiated by electrical waves of excitation
We have subdivided all possible action potential (AP) shapes into the following 3 types: normal APs, APs with one or more early after depolarizations (EADs), and oscillatory APs. In all these cases we find, in consonance with our expectations, that increases in ICaL or INaCa and decreases in IKr or IKs promote transition from normal APs to those with EADs and to APs with oscillations
In this paper we have presented a comprehensive numerical study of 2D wave patterns, which are generated by cells that produce EAD responses
Summary
The mechanical pumping of the heart is initiated by electrical waves of excitation. The abnormal propagation of such waves may result in cardiac arrhythmias which disrupt the normal pattern of cardiac contraction and can, cause cardiac arrest and sudden cardiac death [1]. We do not know yet the exact mechanisms by which such arrhythmias occur in the human heart, several factors have been shown to be correlated with increases in the incidence of arrhythmias One such factor is the onset of excitations of cardiac cells with an abnormal time course of the action potential (AP), such as early after depolarizations (EADs) [2,3,4]. An EAD is defined as a reversal of the action potential before the completion of its repolarization It can occur in many forms of genetic defects such as the long QT syndrome [5,6,7], under the action of pharmacological agents as a result of cardiotoxicity [8,9], and in several other conditions [10,11]. The mechanisms of how abnormal excitations result in arrhythmias is still a widely studied subject because many questions remain unanswered
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