ExperimentalCombined blockade of early and late activated atrial potassium currents suppresses atrial fibrillation in a pig model of obstructive apnea
Introduction
Patients with atrial fibrillation (AF) show a high prevalence of obstructive sleep apnea (OSA), ranging from 32% to 49%.1, 2, 3 Patients with untreated OSA have a higher recurrence of AF after cardioversion and after pulmonary vein antrum isolation.4, 5, 6, 7 Previously, we described atrial electrophysiological changes in a pig model for obstructive apneas.8 Increased susceptibility to AF was caused by a pronounced shortening of the atrial effective refractory period (AERP) and monophasic action potentials (MAP) in the pig right atrium as a response to applied negative tracheal pressure (NTP). NTP occurs in patients with OSA due to diaphragmatic contraction during upper airway obstruction and results in a negative intrathoracic pressure and increased transmural pressure gradients.9, 10, 11 Vagal activity was identified as the major mechanism involved in NTP-induced AERP shortening in this model, since NTP-induced AERP shortening, NTP-induced MAP shortening, and AF inducibility were completely prevented by atropine. Acetylcholine-dependent potassium channels are thought to be one of the most relevant components by which vagal tone induces AERP shortening in the atrium.12 The aim of this study was to investigate the effect of the blockade of different potassium channels on NTP-induced AERP shortening, NTP-induced MAP shortening, and AF inducibility during obstructive events. We tested the effect of the blockade of the early activated potassium currents IKur (ultrarapid delayed rectifier potassium current) and Ito (transient outward current) by AVE011813 compared with the blockade of the late activated potassium currents IKr (the rapid component of delayed rectifier potassium current) by sotalol14 on AERP, MAP, and AF inducibility during normal breathing and during tracheal obstruction with applied NTP. Since AERP shortening induced by NTP is vagally mediated and involves acetylcholine-sensitive potassium channels (KACh), we tested the antiarrhythmic effects of the multichannel blocker amiodarone, which has been shown to block KAch channels in therapeutic concentrations.15
Section snippets
Methods
All animal studies conform with the Guidelines for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication no. 85-23, revised 1996).
Twenty-one closed-chest male castrated pigs (25–30 kg) of the German Landrace were anesthetized with 20% urethane (0.8 mL/kg intravenous load, 0.4 mL/kg/h maintenance) and 4% alpha-chloralose (0.4 mL/kg intravenous load, 0.1 mL/kg/h maintenance). The pigs were instrumented as described elsewhere.8 Briefly, a
Electrophysiological effects of amiodarone, AVE0118, and sotalol during normal breathing
Figure 2 shows the separate and combined effects of low-dose amiodarone and atropine (A), of high-dose amiodarone and vagotomy (B), and of AVE0118 and sotalol (C and D) on the atrial refractory period during normal breathing. Low-dose amiodarone, high-dose amiodarone, AVE0118, and sotalol alone increased the AERP by 7.2 ± 3.2, 11.1 ± 2.1, 10.8 ± 1.7, and 25.8 ± 4.2 ms, respectively. The AERP-prolonging effect of amiodarone, AVE0118, and sotalol during normal breathing at baseline and at the end
Discussion
In a pig model simulating the effect of obstructive apneas on the atrium, we showed that the combined blockade of the early activated potassium currents IKur/Ito (AVE0118) and the late activated potassium current IKr (sotalol) could attenuate NTP-induced AERP shortening, NTP-induced MAP shortening, and AF inducibility. By contrast, the IKur/Ito- or the IKr-blocker alone was not effective. Surprisingly, amiodarone, which blocks multiple potassium currents including the acetylcholine-dependent
Limitations
We applied a premature beat to induce AF. In some animals, we observed that AF was induced by spontaneous atrial premature beats, but this spontaneous induction of AF was too rare for a systematic evaluation. A further limitation is that our investigations were made at a single fixed anatomical position in the right atrium. AERP measurement in the left atrium and the investigation of inhomogeneity in conduction, conduction velocity, or spatial distribution of refractoriness in the atrium would
Conclusion
In a pig model of obstructive apneas, we showed that the combination of a blocker of the early activated potassium current IKur/Ito (AVE0118) and a blocker of the late activated potassium current IKr (sotalol) could reduce NTP-induced AERP shortening and MAP shortening, AF inducibility, and AF duration. By contrast, the IKr- or IKur/Ito-blocker alone was not effective. Surprisingly, amiodarone, a known blocker of the acetylcholine-dependent potassium channel, did not prevent NTP-induced AERP
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Klaus Wirth is employed by Sanofi-Aventis.