AVE0118, blocker of the transient outward current (Ito) and ultrarapid delayed rectifier current (IKur), fully restores atrial contractility after cardioversion of atrial fibrillation in the goat

  • De Haan S
  • Greiser M
  • Harks E
 et al. 
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Abstract

BACKGROUND: The loss of atrial contractile function after cardioversion of atrial fibrillation (AF) contributes to the thromboembolic risk associated with AF. The newly developed blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)) AVE0118 prolongs atrial action potential duration and might therefore enhance atrial contractility. We compared the ability of AVE0118 to restore atrial contraction after cardioversion of AF with the efficacy of conventional positive inotropic compounds in the goat model of AF. METHODS AND RESULTS: Eighteen goats were chronically instrumented with epicardial electrodes, a pressure transducer in the right atrium, and piezoelectric crystals to measure right atrial diameter. Atrial contractility and refractoriness and QT duration were measured before and after 1 week (3 to 8 days) of AF induced by repetitive burst pacing. The measurements were repeated after administration of digoxin (0.02 mg/kg), dobutamine (5 microg x kg(-1) x min(-1)), the Ca2+ sensitizer EMD57033 (1 mg x kg(-1) x min(-1)), the L-type Ca2+ channel agonist BayY5959 (0.1 mg x kg(-1) x min(-1)), and AVE0118 (0.01 to 0.2 mg x kg(-1) x min(-1)). The effect of AVE0118 on the configuration of atrial monophasic action potentials was determined for comparison. After 1 week of AF, atrial contractility during sinus rhythm or slow atrial pacing was reduced to

Author-supplied keywords

  • Electrophysiology
  • Fibrillation
  • Inotropic agents
  • Ion channels
  • Stroke

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Authors

  • Sunniva De Haan

  • Maura Greiser

  • Erik Harks

  • Yuri Blaauw

  • Arne Van Hunnik

  • Sander Verheule

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