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Effect of selective...
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Fenner, Merle FriederikeUniversity of Copenhagen
(författare)
Effect of selective IK,ACh inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation
- Artikel/kapitelEngelska2020
Förlag, utgivningsår, omfång ...
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2020-06-24
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Wiley,2020
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17 s.
Nummerbeteckningar
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LIBRIS-ID:oai:lup.lub.lu.se:25565699-72d1-4acb-b46a-b5c51aa90a2c
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https://lup.lub.lu.se/record/25565699-72d1-4acb-b46a-b5c51aa90a2cURI
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https://doi.org/10.1111/bph.15100DOI
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Språk:engelska
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Sammanfattning på:engelska
Ingår i deldatabas
Klassifikation
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Ämneskategori:art swepub-publicationtype
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Ämneskategori:ref swepub-contenttype
Anmärkningar
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Background and Purpose: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, IK,ACh may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specific IK,ACh inhibitor, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), were characterised for the first time in vitro and investigated in horses with persistent AF. Experimental Approach: The pharmacological ion channel profile of XAF-1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug-induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction. Key Results: XAF-1407 potently and selectively inhibited Kir3.1/3.4 and Kir3.4/3.4, underlying the IK,ACh current. XAF-1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (~20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened atrioventricular-nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min of drug infusion was observed, however, without any evidence of ventricular arrhythmia. Conclusion and Implications: XAF-1407 efficiently cardioverted sustained tachypacing-induced AF of short duration in horses without notable side effects. This supports IK,ACh inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Carstensen, HelenaUniversity of Copenhagen
(författare)
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Dalgas Nissen, SarahUniversity of Copenhagen
(författare)
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Melis Hesselkilde, EvaUniversity of Copenhagen
(författare)
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Scott Lunddahl, ChristineUniversity of Copenhagen
(författare)
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Adler Hess Jensen, MajaUniversity of Copenhagen
(författare)
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Loft-Andersen, Ameli VictoriaUniversity of Copenhagen
(författare)
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Sattler, Stefan MichaelUniversity Hospital Munich,Ludwig-Maximilian University of Munich,Copenhagen University Hospital
(författare)
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Platonov, PyotrLund University,Lunds universitet,Electrocardiology Research Group - CIEL,Forskargrupper vid Lunds universitet,Lund University Research Groups,Skåne University Hospital(Swepub:lu)kard-ppl
(författare)
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El-Haou, SaidXention Ltd
(författare)
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Jackson, ClaireXention Ltd
(författare)
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Tang, RaymondXention Ltd
(författare)
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Kirby, RobertXention Ltd
(författare)
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Ford, JohnXention Ltd
(författare)
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Schotten, UlrichMaastricht University
(författare)
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Milnes, JamesXention Ltd
(författare)
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Svane Sørensen, UlrikAcesion Pharma
(författare)
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Jespersen, ThomasUniversity of Copenhagen
(författare)
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Buhl, RikkeUniversity of Copenhagen
(författare)
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University of CopenhagenUniversity Hospital Munich
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:British Journal of Pharmacology: Wiley177:16, s. 3778-37940007-11881476-5381
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Fenner, Merle Fr ...
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Carstensen, Hele ...
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Dalgas Nissen, S ...
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Melis Hesselkild ...
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Scott Lunddahl, ...
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Adler Hess Jense ...
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Loft-Andersen, A ...
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Platonov, Pyotr
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El-Haou, Said
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Jackson, Claire
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Tang, Raymond
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Kirby, Robert
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Ford, John
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Schotten, Ulrich
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Milnes, James
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Svane Sørensen, ...
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Jespersen, Thoma ...
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Buhl, Rikke
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