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Pharmacological Evaluation of Gap Junction Modifying Antiarrhythmic Peptides For The Treatment of Atrial Fibrillation

Ketil Haugan 

Summary

Atrial fibrillation (AF) is the most commonly occurring sustained arrhythmia in the Western patient population. AF is a serious disorder associated with an increased risk of stroke, morbidity and mortality. The currently available antiarrhythmic drugs used in the treatment of AF have limited efficacy and are associated with side effects. Thus, there is a large unmet clinical need for efficacious and safe antiarrhythmic drugs for the treatment of AF. Gap junction modifying antiarrhythmic peptides (AAP) are efficacious in experimental models of VT, and currently the AAP analogue rotigaptide is in clinical development for the treatment of ischemia induced VT. However, the therapeutic potential of gap junction modifying compounds in the treatment of AF has not been explored. The purpose of this thesis was to perform a pharmacological evaluation of gap junction modifying AAP´s for their use in the treatment of AF.

First a series of in vitro studies were performed using isolated rat atrial strips to examine the electrophysiological effects of rotigaptide. Rotigaptide concentration dependently prevented metabolic stress induced atrial conduction velocity (CV) slowing without affecting CV during physiological conditions. Moreover, rotigaptide rapidly reverted established atrial CV slowing in isolated atrial strips. Rotigaptide had no effect on atrial contractility, had no significant HERG channel blocking activity, and did not bind to a panel of 80 different receptors and ion channels. After completing the in vitro studies a series of in vivo studies was performed. In a rat model of asphyxia induced AF, the AAP analogue AAP10 had no effect on AF inducibility and sustainability. Rotigaptide exerted significant antiarrhythmic effects in a dog model of selective atrial ischemia induced AF. In this model the antiarrhythmic effect was associated with a prevention of ischemia induced conduction slowing. In a rabbit model of chronic volume overload induced atrial dilatation and in dog models of atrial and ventricular tachypacing induced AF, rotigaptide significantly increased atrial CV without affecting overall AF inducibility.

To conclude, treatment with gap junction modifying compounds appears to be efficacious in preventing AF when ischemia or metabolic stress is the cause of the arrhythmia. In models of AF where the arrhythmia substrate is of a more chronic nature, rotigaptide increases CV without affecting AF inducibility. Clinical studies are warranted to determine the potential of rotigaptide and analogues in humans with different arrhythmia substrates.