Abstract 2865: Ventricular Rate Control using the Adenosine Receptor Agonist CVT510 in the Goat Model of Atrial Fibrillation: Efficacy During Exercise and Synergistic Effects with Metoprolol
Background: Rate control is important in the management of atrial fibrillation (AF). Selective A1-adenosine receptor agonists might reduce ventricular rate during AF by activation of G-protein coupled inward rectifier currents and by antagonizing β-adrenergic effects due to activation of inhibitory G proteins. Unlike β-blockers and Ca2+-antagonists, A1-receptor agonists do not exert a negative inotropic effect on the ventricle. In the goat model of persistent AF, we investigated the effect of the A1-receptor agonist CVT-510 on ventricular rate during rest and exercise and whether CVT-510 and the β-receptor antagonist metoprolol act synergistically on ventricular rate.
Methods & Results: In 12 chronically instrumented goats, AF was induced by repetitive burst pacing. Bolus injections of CVT-510 dose-dependently prolonged the ventricular cycle length during AF (RRAF) within 5 min after administration from 345 ± 28ms to 405 ± 32ms (1μg/kg), 485 ± 38ms (3μg/kg), and to 545 ± 47ms (10μg/kg), respectively (p < 0.05, n = 8). Continuous infusion of CVT-510 (0.2μg/kg/min) prolonged RRAF both in the presence and absence of low dose metoprolol (3μg/kg/min). However, the effect was significantly more pronounced in the presence of metoprolol (n = 6, p < 0.05, ANOVA). CVT-510 increased QT-time from 198 ± 25ms to 231 ± 31ms alone and from 224 ± 25ms to 270 ± 11ms with metoprolol. This increase was within the expected rate-related changes. During rest, continuous infusion of metoprolol (30μg/kg/min), CVT-510 (0.2μg/kg/min), and digoxin (1.5mg) prolonged RRAF to a similar extent (+207 ± 41ms, +211 ± 49ms, +188 ± 32ms, n.s.). RRAF shortening during exercise (treadmill at 3mph) was comparable with metoprolol (-185 ± 23ms) and CVT-510 (-226 ± 56ms, n.s.) but more pronounced with digoxin (-303 ± 58ms, p < 0.05).
Conclusions: The A1 receptor agonist CVT-510 provides effective rate control during AF at rest and during exercise. The rate effect of CVT-510 during exercise is superior to digoxin and at least as pronounced as the effect of metoprolol. The action of CVT-510 and metoprolol on ventricular rate was synergistic. A1 receptor agonists may serve as potent therapeutic agents for rate control in AF avoiding a negative inotropic effect on the ventricle.