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PO1-2-80

Dynamical mechanism of multi-stable early afterdepolarizations in a ventricular myocyte elicited by administration of class III antiarrhythmic agents: in silico study

[Speaker] Kunichika Tsumoto:1
[Co-author] Yasutaka Kurata:2, Kazuharu Furutani:3, Yoshihisa Kurachi:1
1:Graduate school of Medicine, Osaka University, Japan, 2:Department of Physiology, Kanazawa Medical University, Japan, 3:Department of Physiology and Membrane Biology, University of California Davis, USA

Some cardiovascular and non-cardiovascular drugs frequently cause prolongation of the cardiac action potential (AP) by unintended inhibition of the rapid component of delayed rectifying K+ current (IKr). Although it is believed that excessive AP prolongation leads to the development of early afterdepolarizations (EADs), the triggering mechanism of EAD-induced ventricular arrhythmias is not yet fully understood. Combining computer simulations with numerical computations based on dynamical system theory, we have investigated dynamical stability changes of AP observed in a paced ventricular myocyte model when the IKr with IKs (slow components of delayed rectifying K+ current), i.e., repolarization reserve, was reduced by the administration of class III antiarrhythmic agents. The blockade of IKr caused the prolongation of APD and an abrupt change in AP configuration. We found that upon reducing IKr, EAD emergence resulted from the dynamical stability change in AP with EADs. This result suggests that the EAD formation was not associated with the configuration change in normal AP (without EADs) through the AP prolongation. Furthermore, reducing in repolarization currents evoked multi-stable dynamics including AP with EADs depended on initial ion circumstances within the myocyte. The AP responses with different AP duration (APD) that underlies multi-stable AP dynamics may increase the local/global heterogeneity of AP repolarization in the ventricle. The EAD-induced arrhythmias with decreases in repolarization currents might be attributable to the APD-variability caused by multi-stable EADs in cardiac AP dynamics.
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