AVE0118，一种瞬时外向电流（I(to)）和超快速延迟整流电流（I(Kur)）的阻滞剂，可在山羊房颤复律后完全恢复心房收缩力。
AVE0118, blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)), fully restores atrial contractility after cardioversion of atrial fibrillation in the goat.
作者信息
de Haan Sunniva, Greiser Maura, Harks Erik, Blaauw Yuri, van Hunnik Arne, Verheule Sander, Allessie Maurits, Schotten Ulrich
机构信息
Department of Physiology, University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands.
出版信息
Circulation. 2006 Sep 19;114(12):1234-42. doi: 10.1161/CIRCULATIONAHA.106.630905. Epub 2006 Aug 28.
BACKGROUND
The loss of atrial contractile function after cardioversion of atrial fibrillation (AF) contributes to the thromboembolic risk associated with AF. The newly developed blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)) AVE0118 prolongs atrial action potential duration and might therefore enhance atrial contractility. We compared the ability of AVE0118 to restore atrial contraction after cardioversion of AF with the efficacy of conventional positive inotropic compounds in the goat model of AF.
METHODS AND RESULTS
Eighteen goats were chronically instrumented with epicardial electrodes, a pressure transducer in the right atrium, and piezoelectric crystals to measure right atrial diameter. Atrial contractility and refractoriness and QT duration were measured before and after 1 week (3 to 8 days) of AF induced by repetitive burst pacing. The measurements were repeated after administration of digoxin (0.02 mg/kg), dobutamine (5 microg x kg(-1) x min(-1)), the Ca2+ sensitizer EMD57033 (1 mg x kg(-1) x min(-1)), the L-type Ca2+ channel agonist BayY5959 (0.1 mg x kg(-1) x min(-1)), and AVE0118 (0.01 to 0.2 mg x kg(-1) x min(-1)). The effect of AVE0118 on the configuration of atrial monophasic action potentials was determined for comparison. After 1 week of AF, atrial contractility during sinus rhythm or slow atrial pacing was reduced to <10%. Digoxin and dobutamine failed to increase atrial contractility. EMD57033 restored 41% and BayY5959 restored 48% of atrial contractility at baseline. BayY5959 significantly prolonged QT duration by 24.7%. AVE0118 enhanced atrial contraction to 156% of the baseline value. The positive inotropic effect was accompanied by a pronounced prolongation of atrial action potential duration and refractoriness, whereas QT duration remained unchanged.
CONCLUSIONS
Conventional positive inotropic drugs showed limited effect on atrial contractility after cardioversion of AF or produced QT prolongation. In contrast, the I(to)/I(Kur) blocker AVE0118 fully restored atrial contraction without proarrhythmic effects on the ventricle.
背景
心房颤动（AF）复律后心房收缩功能丧失会增加与AF相关的血栓栓塞风险。新开发的瞬时外向电流（I(to)）和超快速延迟整流电流（I(Kur)）阻滞剂AVE0118可延长心房动作电位时程，因此可能增强心房收缩力。我们在山羊AF模型中比较了AVE0118在AF复律后恢复心房收缩的能力与传统正性肌力化合物的疗效。
方法与结果
18只山羊长期植入心外膜电极、右心房压力传感器和压电晶体以测量右心房直径。在通过重复短阵起搏诱导AF 1周（3至8天）前后，测量心房收缩力、不应期和QT间期。在给予地高辛（0.02 mg/kg）、多巴酚丁胺（5 μg·kg⁻¹·min⁻¹）、Ca²⁺增敏剂EMD57033（1 mg·kg⁻¹·min⁻¹）、L型Ca²⁺通道激动剂BayY5959（0.1 mg·kg⁻¹·min⁻¹）和AVE0118（0.01至0.2 mg·kg⁻¹·min⁻¹）后重复测量。为作比较，测定AVE0118对心房单相动作电位形态的影响。AF 1周后，窦性心律或缓慢心房起搏时的心房收缩力降至<10%。地高辛和多巴酚丁胺未能增加心房收缩力。EMD57033使心房收缩力恢复至基线的41%，BayY5959使心房收缩力恢复至基线的48%。BayY5959使QT间期显著延长24.7%。AVE0118使心房收缩增强至基线值的156%。正性肌力作用伴有心房动作电位时程和不应期的显著延长，而QT间期保持不变。
结论
传统正性肌力药物对AF复律后的心房收缩力作用有限或导致QT间期延长。相比之下，I(to)/I(Kur)阻滞剂AVE0118可完全恢复心房收缩，且对心室无促心律失常作用。
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