Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca2+-Activated K+ Channels in Pigs.

Jonas Goldin Diness,Joana Larupa Santos,Morten Grunnet,Carlotta Citerni,Daniel Rafael Peter Sauter,Jesper Hastrup Svendsen,Thomas Jespersen,Søren-Peter Olesen,Lasse Skibsbye,Sofia Hammami Bomholtz,Pia Lundegaard,Ulrik S Sørensen,Bo Hjorth Bentzen,Rafel Simó-Vicens

doi:10.1161/circep.117.005125

Jonas Goldin Diness, Joana Larupa Santos + Show 12 more

Open Access

https://doi.org/10.1161/circep.117.005125

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Abstract

Evidence has emerged that small-conductance Ca2+-activated K+ (SK) channels constitute a new target for treatment of atrial fibrillation (AF). SK channels are predominantly expressed in the atria as compared with the ventricles. Various marketed antiarrhythmic drugs are limited by ventricular adverse effects and efficacy loss as AF progresses. A total of 43 pigs were used for the studies. AF reversion in conscious long-term tachypaced pigs: Pigs were subjected to atrial tachypacing (7 Hz) until they developed sustained AF that could not be reverted by vernakalant 4 mg/kg (18.8±3.3 days of atrial tachypacing). When the SK channel inhibitor AP14145 was tested in these animals, vernakalant-resistant AF was reverted to sinus rhythm, and reinduction of AF by burst pacing (50 Hz) was prevented in 8 of 8 pigs. Effects on refractory period and AF duration in open chest pigs: The effects of AP14145 and vernakalant on the effective refractory periods and acute burst pacing-induced AF were examined in anaesthetized open chest pigs. Both vernakalant and AP14145 significantly prolonged atrial refractoriness and reduced AF duration without affecting the ventricular refractoriness or blood pressure in pigs subjected to 7 days atrial tachypacing, as well as in sham-operated control pigs. SK currents play a role in porcine atrial repolarization, and pharmacological inhibition of these with AP14145 demonstrates antiarrhythmic effects in a vernakalant-resistant porcine model of AF. These results suggest SK channel blockers as potentially interesting anti-AF drugs.

Highlights

Evidence has emerged that small-conductance Ca2+activated K+ (SK) channels constitute a new target for treatment of atrial fibrillation (AF)
In healthy pigs and pigs that had been subjected to 1-week AT, both vernakalant and AP14145 prolonged the AERP and reduced the duration of acutely induced AF while not significantly prolonging the LV ERP or showing other signs of ventricular effects
In an advanced pig model of long-term AT-induced sustained AF where clinically relevant doses of vernakalant could no longer convert the AF to SR, AP14145 was able to convert the pigs to SR and protect against reinduction of AF

Summary

Methods

Effects of AP14145 on hSK3 (KCa2.3) and hERG (hKV11.1) were investigated by automated patch clamp (Qpatch; Biolin Scientific, Sophion, Denmark) as previously described.[19] Likewise, the effect on rNaV1.5 was evaluated as earlier described[20] but with a modified voltage protocol so that rNaV1.5 currents were elicited with 1-second interval by a 50-ms depolarizing step to −20 mV from a holding potential of −120 mV (a total of 80 pulses). Effect of AP14145 on L-type calcium channels was investigated by automated patch clamping (Qpatch; Biolin Scientific) using a hCaV 1.2 stable cell line (α1C, β2C, and α2delta; SB Drug Discovery, Glasgow, United Kingdom). Off-target effects on Kir3.1/Kir3.4 (IKACh), KV1.5 (IKur), KV7.1/KCNE1 (IKs), KV4.3/KChiP2 (Ito), and Kir2.1 (IK1) were investigated using 2-electrode voltage-clamp experiments on Xenopus laevis oocytes expressing the relevant channels.[19] For further details, please see Data Supplement.

Results

Discussion

Conclusion