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Reduced ventricular proarrhythmic potential of the novel combined ion-channel blocker AZD1305 versus dofetilide in dogs with remodeled hearts.

Abstract

BACKGROUND
AZD1305 is an investigational antiarrhythmic agent for management of atrial fibrillation. It blocks various cardiac ion currents at different potencies and has atrial-predominant electrophysiological effects. We investigated the electrophysiological and proarrhythmic effects of AZD1305 versus dofetilide in dogs with chronic complete atrioventricular block and myocardial hypertrophic remodeling.
METHODS AND RESULTS
AZD1305 was administered to anesthetized mongrel dogs before and >2 weeks after the induction of atrioventricular block and ventricular and atrial electrophysiological parameters were assessed. In all dogs, the selective I(Kr) blocker dofetilide was used to examine susceptibility to acquired torsades de pointes in chronic atrioventricular block and for comparison. At normal sinus rhythm, AZD1305 increased QT and RR intervals from 290±7 to 397±15 ms (+37%, P<0.0001) and from 603±22 to 778±32 ms (+29%, P=0.002), respectively. In the same animals at chronic atrioventricular block, AZD1305 increased the QT interval from 535±28 to 747±36 ms (+40%, P<0.0001), similar to the QT prolongation by dofetilide (511±22 to 703±45 ms [+38%, P<0.0001]). AZD1305 slightly slowed the idioventricular rhythm. Whereas all (n=14) chronic atrioventricular block animals exhibited torsades de pointes on dofetilide, the arrhythmia was induced in only 4 of 11 dogs after AZD1305. Beat-to-beat variability of left-ventricular monophasic-action-potential duration increased after dofetilide (2.3±0.2 to 6.3±0.7 ms; P<0.0001) but not after AZD1305 (2.8±0.3 to 3.7±0.3 ms; P=0.20) despite similar left-ventricular monophasic-action-potential duration prolongations.
CONCLUSIONS
Despite causing similar degrees of repolarization delay as the selective I(Kr) blocker dofetilide, the combined ion-channel blocker AZD1305 induces less repolarization instability and has a lower ventricular proarrhythmic potential in the remodeled dog heart.

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  • Authors

    Johnson DM, de Jong MM, Crijns HJ, Carlsson LG, Volders PG

    Institution

    Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.

    Source

    Circulation. Arrhythmia and electrophysiology 5:1 2012 Feb 1 pg 201-9

    MeSH

    Animals
    Atrioventricular Block
    Azabicyclo Compounds
    Carbamates
    Disease Models, Animal
    Dogs
    Electrophysiologic Techniques, Cardiac
    Female
    Follow-Up Studies
    Heart Rate
    Male
    Phenethylamines
    Potassium Channel Blockers
    Sulfonamides
    Treatment Outcome
    Ventricular Remodeling

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22080293