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(Circulation. 2006;114:110-118.)
© 2006 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Effects of the Gap Junction Modifier Rotigaptide (ZP123) on Atrial Conduction and Vulnerability to Atrial Fibrillation

Jose M. Guerra, MD^*; Thomas H. Everett, IV, PhD^*; Ken W. Lee, MD, MS; Emily Wilson, BS; Jeffrey E. Olgin, MD

From Cardiac Electrophysiology, Division of Cardiology and the Cardiovascular Research Institute, University of California, San Francisco.

Correspondence to Jeffrey E. Olgin, MD, University of California, San Francisco, 500 Parnassus Ave, MU East 4, Box 1354, San Francisco, CA 94143. E-mail olgin{at}medicine.ucsf.edu

Received December 5, 2005; revision received May 3, 2006; accepted May 5, 2006.

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.

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