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


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.
Guerra
Jose M
JM
Cardiac Electrophysiology, Division of Cardiology and the Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
Everett
Thomas H
TH
Lee
Ken W
KW
Wilson
Emily
E
Olgin
Jeffrey E
JE
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000517:prevention & control*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004285:Dogs; D017629:Gap Junctions / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects*; D009842:Oligopeptides / Q000627:therapeutic use*; D017180:Tachycardia, Ventricular / Q000188:drug therapy
D000889:Anti-Arrhythmia Agents; D009842:Oligopeptides; C477643:rotigaptide