Gap junction modifying antiarrhythmic peptides: Therapeutic potential in atrial fibrillation

Atrial fibrillation (AF) is the most commonly occurring sustained arrhythmia in clinical practice. AF is a serious disorder associated with an increased risk of stroke, morbidity and mortality, and the number of patients is estimated to more than double within the next 4 decades. The currently available antiarrhythmic drugs (AADs) have limited efficacy and are associated with serious side effects, of which the potentially lethal ventricular proarrhythmias are one of the major concerns. Thus, there is a large unmet clinical need for effective and safe AADs for the treatment of AF. Gap junction-modifying antiarrhythmic peptides (AAPs) that act by increasing cardiac gap junction intercellular communication represent a new class of AADs. Rotigaptide is a synthetic AAP analogue that prevents metabolic stress-induced atrial conduction velocity (CV) slowing and rapidly reverts established atrial CV slowing in vitro. Rotigaptide has contrasting effects in large animal models of AF. In dog models of atrial and ventricular tachypacing-induced AF, rotigaptide significantly increases atrial CV, but does not inhibit electrically induced AF. However, in dog models of ischemia-related AF and chronic atrial dilatationinduced AF, rotigaptide has significant antiarrhythmic effects. Rotigaptide also has a favorable safety profile. In this paper we will review the experimental and clinical data suggesting a role for this new class of gap junction-modifying AAPs for the treatment of AF.