Anti‐fibrillatory effects of F17727, a new IKur blocker, in rats and rabbits with myocardial infarction or heart failure (652.17)

Abstract

Atrial fibrillation (AF) can be triggered by myocardial infarction (MI) or heart failure (HF). The blockade of the ultra‐rapid outward rectifier potassium current IKur is an attractive goal to control the repolarization of cardiac atria. F17727 was evaluated in patch‐clamp assays, in rat post‐MI and in HF in rabbit and dog. F17727 blocked human IKur (IC50=1.8µM) and did not impact IKr, IKs, INa. In rats 2 months after coronary artery ligation, the left atria surface increased by 50‐150%; transœsophagial electrical bursts induced AF which lasted 5‐21s in vehicle‐MI rats but lower than 5s in sham. An acute iv treatment by F17727 (2.5 and 5mg/kg) significantly reduced AF induction at the level of sham. In rabbits, 2‐week left atria tachypacing up to 1200bpm triggered electrical and structural remodeling; electrical stimuli induced AF. An acute iv treatment by F17727 (racemate, 2.5mg/kg) reduced AF (mean spontaneous and induced AF duration of 4±4s and 82±49s) when compared to vehicle (165±75s and 261±45s respectively). In dogs with HF, F17727 did not reduce electrical stimuli‐induced AF and the role of IKur in atrial repolarization is questionable. Hence the selective IKur blocker F17727 prevents the occurrence of AF induction in rats and rabbits with different AF substrates during MI and HF. The F17727 pharmacological profile reinforces the interest of IKur blockade as a rhythm control strategy for AF treatment in humans.