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A novel antiarrhythmic principle in the treatment of cardiac disorders

Thomas Diness

Summary

A range of different ion channels, selectively allowing passage of specific ions, are responsible for shaping the action potential of the cardiac cells. In this thesis, particular focus will be given to the human ether-a-go-go-relatedĖgene (hERG) potassium channel. This channel is involved in termination of the cardiac action potential. It conducts potassium in the final phase of the action potential leading to efflux and hereby hyperpolarization towards the resting membrane potential of the cardiac cells. Dysfunction of the hERG channel can be caused by inherited mutations or by drugs blocking the channel pore. This can lead to a delayed repolarization of the cardiac cells, which is reflected as a prolonged QT interval on the body surface electrocardiogram. Patients with long QT intervals are known to be predisposed to potentially life threatening ventricular arrhythmias. In theory, compounds that can reduce a prolonged QT interval could have antiarrhythmic properties in such patients.  

 

This thesis comprises a biophysical characterization in heterologous expression systems of two of the first published hERG channel activators, NS1643 and NS3623. Further, the effect on isolated cardiac cells and tissue preparations regarding the action potential duration and the cell excitability is investigated. These investigations show that the NS-compounds reduce the action potential duration and stabilizes the cardiac cells against afterdepolarizations induced by post-repolarization stimuli. To take this further, the acute antiarrhythmic effect of NS1643, was investigated in two clinically-relevant in vivo models of arrhythmia associated with long QT intervals. In both models, NS1643 was found to reduce the prolonged QT interval and reduce/suppress the arrhythmic activity.  

 

In contrast to hERG mutations causing long QT, one hERG mutation, also associated with ventricular arrhythmias, has been demonstrated to increase repolarization causing a short QT interval. As one potential unwanted effect of the hERG agonists is the introduction of such a short QT phenotype, a thorough biophysical characterization was performed to compare the hERG short QT mutation with the effect of NS1643 on a wild type hERG channel. It was  demonstrated that very important differences exists and, hence, that NS1643 cannot simply be regarded as a compound introducing a similar short QT syndrome as the one related to ventricular arrhythmias. In conclusion, evidence has been presented that favors hERG activation by mechanisms identical to the NS-compoundís as a potential antiarrhythmic drug treatment in long QT interval patients.