Published Online
on February 13, 2009

A more recent version of this article appeared on April 1, 2009

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Original Article

Effects of Chronic Gap Junction Conduction-Enhancing Antiarrhythmic Peptide GAP-134 Administration on Experimental Atrial Fibrillation in Dogs

Gabriel Laurent¹; Howard Leong-Poi²; Iqwal Mangat²; Gordon W. Moe²; Xudong Hu¹; Petsy Pui-Sze So¹; Emidio Tarulli³; Andrew Ramadeen¹; Eric I. Rossman⁴; James K. Hennan⁴ and Paul Dorian^2,5

¹ St. Michael's Hospital, Toronto;
² St. Michael's Hospital and University of Toronto;
³ University of Toronto;
⁴ Wyeth Research

⁵ E-mail: dorianp{at}smh.toronto.on.ca

Background—Abnormal intercellular communication caused by connexin dysfunction may contribute to atrial fibrillation (AF). The present study assessed the effect of the gap junction conduction-enhancing antiarrhythmic peptide GAP-134 on AF inducibility and maintenance in a dog model of atrial cardiomyopathy.

Methods and Results—Twenty four dogs subject to simultaneous atrio-ventricular pacing (220 bpm for 14 days (d)) were randomly assigned to placebo treatment (PACED-CTRL; 12 dogs) or oral GAP-134 (2.9 mg/kg BID; PACED-GAP-134; 12 dogs) starting on day 0. UNPACED-CTRL (4 dogs) and UNPACED-GAP-134 (4 dogs) served as additional control groups. Change in left atrial systolic area (LASA) from baseline to 14 d was calculated using transoesophageal echocardiography. At 14 d, animals underwent an open chest electrophysiological study (EPS). PACED-CTRL dogs (vs. UNPACED-CTRL) had a shorter estimated LA wavelength (WL) (8.0±1.4cm (X + SD) vs. 24.4±2.5cm, p<0.05), and a greater AF vulnerability (mean AF duration: 1588±329 vs. 25±34s, p<0.05). Oral GAP-134 had no effect on AF vulnerability in UNPACED dogs. Compared to PACED-CTRL dogs, PACED-GAP-134 dogs had a longer estimated LA WL (10.2±2.8 vs. 8.0±1.4cm, respectively, p<0.05). Oral GAP-134 did not significantly reduce AF inducibility or maintenance in the entire group of 24 PACED dogs; in a subgroup of dogs (n=11) with less than 100%, increase in LASA, oral GAP-134 reduced AF induction from 100% to 40%, and mean AF duration from 1737±120 s to 615±280s (p<0.05).

Conclusions—Oral GAP-134 reduces pacing induced decrease in LA wavelength, and appears to attenuate AF vulnerability in dogs with less atrial mechanical remodeling. Gap junction modulation may affect AF in some circumstances.

Key Words: cardiomyopathy • Atrial Fibrillation • Gap Junction

Related Article

Effects of Chronic Gap Junction Conduction–Enhancing Antiarrhythmic Peptide GAP-134 Administration on Experimental Atrial Fibrillation in Dogs

Gabriel Laurent, Howard Leong-Poi, Iqwal Mangat, Gordon W. Moe, Xudong Hu, Petsy Pui-Sze So, Emidio Tarulli, Andrew Ramadeen, Eric I. Rossman, James K. Hennan, and Paul Dorian
Circ Arrhythm Electrophysiol 2009 2: 171-178. [Abstract] [Full Text] [PDF]

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