Effects of chronic gap junction conduction-enhancing antiarrhythmic peptide GAP-134 administration on experimental atrial fibrillation in dogs.
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.


RESULTS
Twenty-four dogs subject to simultaneous atrioventricular pacing (220 bpm for 14 days) 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 (LA) systolic area from baseline to 14 days was calculated using transoesophageal echocardiography. At 14 days, animals underwent an open-chest electrophysiological study. PACED-CTRL dogs (versus UNPACED-CTRL) had a shorter estimated LA wavelength (8.0+/-1.4 versus 24.4+/-2.5 cm, P<0.05) and a greater AF vulnerability (mean AF duration, 1588+/-329 versus 25+/-34 seconds, P<0.05). Oral GAP-134 had no effect on AF vulnerability in UNPACED dogs. Compared with PACED-CTRL dogs, PACED-GAP-134 dogs had a longer estimated LA wavelength (10.2+/-2.8 versus 8.0+/-1.4 cm, 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 LA systolic area, oral GAP-134 reduced AF induction from 100% to 40% and mean AF duration from 1737+/-120 to 615+/-280 seconds (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.
Laurent
Gabriel
G
Keenan Research Center, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario M5B 1W8, Canada.
Leong-Poi
Howard
H
Mangat
Iqwal
I
Moe
Gordon W
GW
Hu
Xudong
X
So
Petsy Pui-Sze
PP
Tarulli
Emidio
E
Ramadeen
Andrew
A
Rossman
Eric I
EI
Hennan
James K
JK
Dorian
Paul
P
D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology*; D001549:Benzamides / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005355:Fibrosis; D017629:Gap Junctions / Q000502:physiology*; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
C541429:1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid; D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D018031:Connexin 43; D011392:Proline