Abstract:
In the course of this project, the effects of the hERG channel mutation N588K on atrial repolar- ization and the predisposition to atrial fibrillation have been analyzed. For this purpose, measured data obtained with whole cell voltage clamp technique of wild-type and mutated hERG channel were implemented in the Courtemanche et al. ionic model. Channel kinetics and density of the model were therefore adjusted using parameter fitting to the measured data. The effects of the mutation in the hERG channel could be analyzed in a single-cell and tissue environment. Hereby, the most relevant factors for cardiac arrhythmias, such as APD, rate dependence, CV, and ERP were determined. The excitation propagation, repolarization and pre- disposition for rotating waves were finally investigated using a schematic anatomical model of the right atrium.The results presented in chapter 5 underline that the proper implementation of measured data in electrophysiological cell models can be affected by the measurement protocol used in the voltage clamp-technique. Since the use of a different pulse duration and return pulse can alter the behavior of the ionic currents, in particular during the recovery from inactivation and deactivation processes, the clamp-protocol used is very important for an accurate analysis of the channel effects on the cell.Further, mutation N588K showed a gain of function effect of IKr caused by the shifted inactivation of the hERG channel towards more positive potentials. In single-cell, this resulted in a significant shortening of the APD to 116 ms. However, the effects of the mutation in tissue were not that strong as in a single-cell. This results from the characteristic behavior of the mutation that shows a dependence on the maximum upstroke reached by depolarization. As a consequence, the effective APD was 220 ms. The ERP was also reduced in the tissue simulations. Combined with the fact that the CV decreases by short BCL, this effect builds a substrate for the initiation and perpetuation of AF. The differences between physiological and mutated case were most visible in the two- dimensional model. Not only the repolarization was shorter, but the mutated model supported the initiation of rotating waves, in contrast to the physiological one. The generated results show that mutation N588K builds, indeed, a substrate that can support the predisposition of AF. For further investigations it is very important to implement measured data which includes the information of the channel processes during recovery from inactivation. This will lead to more accurate analysis about the effects of the mutation, and with it to a better understanding of the electrical behavior underlying cardiac arrhtymia.Finally, a complete three-dimensional anatomical model should be used to further analyze the effect of mutation N588K on the perpetuation of rotating waves. The model used in this work did not include important factors like curvature or sharp edges, which play a very important role for the conduction velocity. In a three-dimensional model the conduction velocity will decrease, resulting in a further shortening of the wavelength. By this way, the model could not only produce one rotating wave, but flutter or fibrillation.