Abstract:

Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting around 1% of the population. Several anti-arrhythmic drugs such as e.g. amiodarone or dronedarone influence cardiac electrophysiology reducing arrhythmias. However, the electrophysiological mechanisms underlying the initiation and persistence of AF are not completely understood yet.Methods: A mathematical model of atrial electrophysiology was modified to simulate the effects of chronic AF (cAF). Furthermore, ion channel conductivities were reduced according to the inhibition caused by two different concentrations of amiodarone and dronedarone. The resulting drug effects were investigated in healthy and cAF single-cells as well as in tissue. In a 1D tissue strand, restitution curves of the effective refractory period (ERP), the conduction velocity (CV) and the wavelength (WL) were computed. Furthermore, persistence of rotors in a 2D tissue patch was analyzed. For this purpose, four rotors were initiated in the cAF patch and then the drug effects were incorporated.Results: Dronedarone and amiodarone prolonged the atrial action potential duration of cAF cells, whereas high concentration of amiodarone slightly shortened it in healthy cells. Furthermore, both drugs increased the ERP and slowed the CV. Dronedarone shows the longer ERP and also a higher CV. As a result, the WL was prolonged by dronedarone and shortened by high concentration of amiodarone. Low concentration of amiodarone did not change the WL. In the 2D tissue patch, dronedarone altered significantly the trajectory of rotors, but did not terminate them.Conclusion: Computer simulations of the effects of antiarrhythmic drugs on cardiac electrophysiology are a helpful tool to better understand the mechanisms responsible for persistence and termination of AF. However, ion current measurement data available in literature show great variability of values depending on the species or temperature. Therefore, integration of drug effects into models of cardiac electrophysiology still needs to be improved.

Abstract:

This work concentrates on in silico methods to investigate the impact of dronedarone on human myocytes. Here, two different atrial cells using the CRN model were simulated: firstly, the model of a healthy and secondly the model of an electrically remodeled myocyte, which possesses the electrophysiological behavior of a myocyte suffering from AF. In order to regard natural fluctuations of the agent, two drug concentrations were taken into account.Dronedarone is a new antiarrhythmic drug, which is similar to its parent agent amiodarone. Therefore, it is a multi channel blocker and is classified as class three antiarrhythmic drug. Nevertheless, properties of all Vaughan-Williams classes are exhibited. Blocking of channels, which is equivalent to a decrease of their conductivity, is dependent on the drug dosage. This link between the drug dosage and the inhibition of the channels is described by the Hill equation. However, only two values are needed to characterize the Hill function. Hence, in order to describe the impact of dronedarone, these values were obtained from literature. But, due to the spread of data, three setups were created. Here, each setup individually describes the effect of the drug.Afterwards, simulations using single cells were carried out, during which the drug related APD prolongations were investigated. Though based on experimental studies, it became clear that the created setups missed data. Therefore, unpublished data of the Kur channel was included, which resulted in much more realistic results. Hence, these expanded setups were also used in the further simulations.During the investigation of the different impacts of the setups on the ERP, CV and WL as well, setup 3 turned out to be the most successful one, since the prolongations were superior to those of the other setups. In contrast, setup 1 is the only one, which was successful in reducing the width of the VW, even though only in case of using the lower drug concentration.Finally, a two-dimensional tissue patch was created, within which four rotatory excitations were artificially placed in order to simulate AF. Thus, the effect of dronedarone on AF could be investigated during a simulation period of about 5 seconds. The investigation included the tracking of the rotor centers as well as the measurement of pseudo ECGs, from which the characteristic frequencies were extracted. Hence, information about the propagation progress as well as the possibility of AF to terminate of its own volition were gained. Unfortunately, no setup was able to terminate one or more rotors, but both the rotor propagation as well as the characteristic frequency were influenced. The biggest decrease of the characteristic frequency and therefore the highest possibility of AF to terminate of its own volition was achieved by using setup 3. The characteristic frequency in case of the higher drug concentration was lowered from 8.98 Hz to 7.81 Hz. Based on this outcome, further simulations with both drug concentrations using setup 3 were started. These simulations lasted 25 seconds, in order to investigate the long-term effect. Yet, no changes of the characteristic frequency appeared.Finally, dronedarone was found to be eventually effective in preventing the onset of AF in electrically remodeled cells and tissue but it is not able to terminate chronic AF.