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Block of I(Kur) by AVE0118 enhances atrial contractility both in patients with sinus rhythm and atrial fibrillation. The positive inotropic effect is atrial-specific and due to the changes of the action potential configuration which enhances Ca2+ entry via reverse mode Na+/Ca2+ exchange.

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 g · kg Ϫ1 · min Ϫ1 ), the Ca

Allessie. Loss of atrial contractility is primary cause of atrial dilatation during first days of atrial fibrillation. Am J Physiol Heart Circ Physiol 287: H2324 -H2331, 2004. First published July 15, 2004 doi: 10.1152/ajpheart.00581.2004.-Atrial fibrillation (AF) induces a progressive dilatation of the atria which in turn might promote the arrhythmia. The mechanism of atrial dilatation during AF is not known. To test the hypothesis that loss of atrial contractile function is a primary cause of atrial dilatation during the first days of AF, eight goats were chronically instrumented with epicardial electrodes, a pressure transducer in the right atrium, and piezoelectric crystals to measure right atrial diameter. AF was induced with the use of repetitive burst pacing. Atrial contractility was assessed during sinus rhythm, atrial pacing (160-, 300-, and 400-ms cycle length), and electrically induced AF. The compliance of the fibrillating right atrium was measured during unloading the atria with diuretics and loading with 1 liter of saline. All measurements were repeated after 6, 12, and 24 h of AF and then once a day during the first 5 days of AF. Recovery of the observed changes after spontaneous cardioversion was also studied. After 5 days of AF, atrial contractility during sinus rhythm or slow atrial pacing was greatly reduced. During rapid pacing (160 ms) or AF, the amplitude of the atrial pressure waves had declined to 20% of control. The compliance of the fibrillating atria increased twofold, whereas the right atrial pressure was unchanged. As a result, the mean right atrial diameter increased by ϳ12%. All changes were reversible within 3 days of sinus rhythm. We conclude that atrial dilatation during the first days of AF is due to an increase in atrial compliance caused by loss of atrial contractility during AF. Atrial compliance and size are restored when atrial contractility recovers after cardioversion of AF. stunning; remodeling; atrial tachyarrhythmias A RELATIONSHIP between atrial size and atrial fibrillation (AF) was first proposed by Fraser and Turner in 1955 (1), who showed that AF was more common in patients with enlarged atria than in patients with normal atrial size. In the 1990s, large prospective trials established left atrial enlargement as an independent risk factor for the development of AF (13,14). Today, it is generally accepted that AF is not only a consequence but also a cause of atrial dilatation. In patients with "lone AF," Sanfilippo et al. (9) demonstrated that AF resulted in progressive atrial dilatation, which in turn, might contribute to the self-perpetuating nature of the arrhythmia.The mechanism of atrial dilatation related to AF is still unclear. It has been proposed that mild impairment of ventricular pump function due to the high ventricular rate during AF might increase end-diastolic ventricular and atrial pressures (12). An alternative explanation might be that the pronounced atrial contractile dysfunction of the atria induced by AF (6, 7, 10) underlies the dilatation of ...

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