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Inhibition of the atrial ultra-rapid delayed rectifier potassium current (IKur) represents a promising therapeutic strategy in the therapy of atrial fibrillation. However, experimental and clinical data on the antiarrhythmic efficacy remain controversial. We tested the hypothesis that antiarrhythmic effects of IKur inhibitors are dependent on kinetic properties of channel blockade. A mathematical description of IKur blockade was introduced into Courtemanche-Ramirez-Nattel models of normal and remodeled atrial electrophysiology. Effects of five model compounds with different kinetic properties were analyzed. Although a reduction of dominant frequencies could be observed in two dimensional tissue simulations for all compounds, a reduction of spiral wave activity could be only be detected in two cases. We found that an increase of the percent area of refractory tissue due to a prolongation of the wavelength seems to be particularly important. By automatic tracking of spiral tip movement we find that increased refractoriness resulted in rotor extinction caused by an increased spiral-tip meandering. We show that antiarrhythmic effects of IKur inhibitors are dependent on kinetic properties of blockade. We find that an increase of the percent area of refractory tissue is the underlying mechanism for an increased spiral-tip meandering, resulting in the extinction of re-entrant circuits. [ABSTRACT FROM AUTHOR]

Acute cardiac ischemia, which is caused by the occlusion of a coronary artery, often leads to lethal ventricular arrhythmias or heart failure. The early diagnosis of this pathology is based on changes of the electrocardiogram (ECG), i.e., mainly shifts of the ST segment. However, the underlying mechanisms responsible for these shifts are not completely understood. Furthermore, clinical observations indicate that some acute ischemia cases can hardly be detected using standard 12-lead ECG only. Therefore, multiscale computer simulations of cardiac ischemia using realistic models of human ventricles were carried out in this work. For this purpose, the transmembrane voltage distributions in the heart and the corresponding body surface potentials were computed with varying transmural extent of the ischemic region at different ischemia stages. Some of the simulated ischemia cases were “ electrically silent,” i.e., they could hardly be identified in the 12-lead ECG. [ABSTRACT FROM AUTHOR]

Inhibition of the atrial ultra-rapid delayed rectifier potassium current (I Kur) represents a promising therapeutic strategy in the therapy of atrial fibrillation. However, experimental and clinical data on the antiarrhythmic efficacy remain controversial. We tested the hypothesis that antiarrhythmic effects of I Kur inhibitors are dependent on kinetic properties of channel blockade. A mathematical description of I Kur blockade was introduced into Courtemanche-Ramirez-Nattel models of normal and remodeled atrial electrophysiology. Effects of five model compounds with different kinetic properties were analyzed. Although a reduction of dominant frequencies could be observed in two dimensional tissue simulations for all compounds, a reduction of spiral wave activity could be only be detected in two cases. We found that an increase of the percent area of refractory tissue due to a prolongation of the wavelength seems to be particularly important. By automatic tracking of spiral tip movement we find that increased refractoriness resulted in rotor extinction caused by an increased spiral-tip meandering. We show that antiarrhythmic effects of I Kur inhibitors are dependent on kinetic properties of blockade. We find that an increase of the percent area of refractory tissue is the underlying mechanism for an increased spiral-tip meandering, resulting in the extinction of re-entrant circuits.