Effects of the gap junction modifier rotigaptide (ZP123) on atrial conduction and vulnerability to atrial fibrillation.

Abstract

BACKGROUND: Altered conduction is associated with increased atrial fibrillation (AF) vulnerability in canine models of chronic mitral regurgitation (MR) and heart failure (HF). Rotigaptide (ZP123) augments gap junction conductance, improving cell-to-cell coupling. We studied the effects of rotigaptide on atrial conduction and AF vulnerability in the canine MR and HF models. METHODS AND RESULTS: Twenty-one dogs in 3 groups were studied: control (n=7), chronic MR induced by mitral avulsion (n=7), and HF induced by ventricular tachypacing (n=7). Epicardial mapping of both atria was performed with a 512-electrode array at baseline and at increasing rotigaptide doses (10, 50, and 200 nmol/L). Conduction velocity increased in both atria in control animals and MR animals (maximum percentage increase: 24+/-5%, 38+/-6% [P<0.001, <0.001] in the left atrium and 19+/-9%, 18+/-3% [P<0.001, <0.001] in the right atrium). Conduction velocity did not change in the left atrium of the HF group and increased minimally in the right atrium (3+/-3%, 17+/-5% [P=NS, P=0.001]). AF duration was increased at baseline in MR and HF animals (control: 16+/-25 seconds, MR: 786+/-764 seconds, HF: 883+/-684 seconds; P=0.013). At 50 nmol/L of rotigaptide, duration of AF markedly decreased in the MR animals (96% reduction, P<0.001), reducing AF duration to that of control animals (control: 9+/-11 seconds, MR: 14+/-16 seconds, HF: 1622+/-355 seconds; P=0.04). CONCLUSIONS: Gap junction modulation with rotigaptide reduces AF vulnerability in a canine MR model of AF to a level similar to control animals but does not affect AF vulnerability in the canine HF model. This may be a novel therapeutic target in some forms of AF.