Effects Of The Gap Junction Modifier, Gap-134, On Conduction And Atrial Fibrillation/Flutter Inducibility In Dogs

Atrial fibrillation (AF) and atrial flutter (AFL), the most common sustained cardiac arrhythmias, are major contributors to cardiovascular morbidity and mortality in the adult population. Current pharmacologic treatment of AF/AFL is only moderately successful and not well tolerated among patients, highlighting an unmet medical need for safer, effective agents. GAP-134 is the first small molecule gap junction modifier developed for the prevention of AF/AFL. In preliminary experiments, this modified antiarrhythmic dipeptide with similar activity to the antiarrhythmic hexapeptide rotigaptide, significantly prevented conduction velocity slowing in rat atrial strips subjected to metabolic stress at 10 nM (5.6±9.4%) and 100 nM (0.4±5.0%) compared to controls (−29.1±5.3%). In the canine sterile pericarditis model, conduction time (CT, n=5) and AF/AFL inducibility (n=9) were measured 2–3 days post-operatively in closed chest studies, using electrodes placed at the right atrial appendage (RAA), the Bachmann’s bundle (BB), and the posterior left atrium (LA). CT, measured between the BB and LA, was significantly faster after GAP-134 infusion (average plasma concentration was 73.1 ng/ml) at RAA pacing rates of 200 bpm (66.2±1.0 ms vs 62.0±1.0 ms; p=2.49E-08), 300 bpm (64.4±0.9 ms vs 61.0±1.3 ms; p=2.67E-03), and 400 bpm (67.2±1.6 ms vs 65.0±1.9 ms; p=0.041). Induction of AF/AFL was attempted using a burst pacing protocol, at all three atrial sites, starting at 500 bpm and increasing at increments of 20 bpm until 800 bpm. The average number of successful AF/AFL inductions per animal was significantly decreased after GAP-134 infusion (2.7±0.6 vs 1.6±0.8; p=0.021), with the total number of inductions being decreased from 24 to 14. Mean AF/AFL duration per induction (603±119 s vs 260±116 s; p=0.021) and mean AF/AFL duration per animal (1364±419 s vs 705±483 s; p=0.049) were also significantly decreased after GAP-134 infusion, with total AF/AFL burden being decreased from 12280 s to 6348 s. In conclusion, GAP-134 shows consistent efficacy on measures of conduction and AF/AFL inducibility in the canine sterile pericarditis model. These findings, along with its oral bioavailability, underscore its potential as a highly effective atrial antiarrhythmic compound.