Inhibition of If in the atrioventricular node as a mechanism for dronedarone's reduction in ventricular rate during atrial fibrillation

被引:24
作者
Verrier, Richard L. [1 ,2 ]
Sobrado, Marcel F. [1 ,3 ]
Pagotto, Vitor P. F. [1 ,3 ]
Kanas, Alexandre F. [1 ,3 ]
Machado, Ananda D. [1 ,3 ]
Varone, Bruno B. [1 ,3 ]
Sobrado, Lucas F. [1 ,3 ]
Nearing, Bruce D. [1 ,2 ]
Zeng, Dewan [4 ]
Belardinelli, Luiz [4 ]
机构
[1] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA
[2] Harvard Univ, Sch Med, Boston, MA 02215 USA
[3] Univ Sao Paulo, Sao Paulo, Brazil
[4] Gilead Sci Inc, Foster City, CA 94404 USA
关键词
I-f inhibition; Human hyperpolarization-activated cyclic nucleotide-gated (HCN) channel; Dronedarone; Atrioventricular node; Atrial fibrillation; Ivabradine; DOUBLE-BLIND; AMIODARONE; IVABRADINE; ARRHYTHMIAS; ZATEBRADINE; SR-33589; RHYTHM; AGENT;
D O I
10.1016/j.hrthm.2013.08.007
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
BACKGROUND In clinical trials, dronedarone lowers ventricular rate during atrial fibrillation (AF). This agent was recently demonstrated to inhibit I-f in the sinoatrial node. OBJECTIVE The purpose of this study was to examine whether dronedarone inhibits I-f at the atrioventricular (AV) node to reduce ventricular rate during AF by slowing conduction at the AV node. METHODS We studied the effects of dronedarone (1.0 mg/kg IV bolus) before and after administration of the I-f inhibitor ivabradine (0.5 mg/kg IV). Ventricular rate, mean arterial pressure, dominant frequency of AF, PR and QT intervals, and atrial (AERP) and ventricular effective refractory periods (VERP) were measured during atrial pacing at 150 bpm in an anesthetized pig model of AF induced by intrapericardial acetylcholine and burst pacing. RESULTS Dronedarone reduced ventricular rate during AF by 22.1% (from 213 +/- 11.1 bpm to 166 +/- 8.3 bpm, P = .01) and increased PR interval by 8.7% (from 173 +/- 5.6 ms to 188 +/- 5.2 ms, P = .001), QT interval by 3.3% (from 272 +/- 6.2 ms to 281 +/- 4.9 ms, P = .05), and AERP and VERP by 6.2% and 11.7%, respectively. ALL other parameters remained unchanged. Dronedarone plasma levels were Low (29 +/- 4 nM), and concentration in tissue was 15- to 21-fold higher than in plasma. Ivabradine reduced ventricular rate during AF by 39.5% (from 200 +/- 14.6 bpm to 121 +/- 20.1 bpm, P = .005) and increased PR interval by 20.4% (from 157 +/- 9.5 ms to 189 +/- 7.4 ms, P < .05). Administration of dronedarone after ivabradine did not further alter these endpoints. CONCLUSION Dronedarone, which is concentrated in myocardial tissue, reduces ventricular rate during AF by slowing AV conduction. Absence of this effect after ivabradine administration implicates I-f inhibition as a mechanism.
引用
收藏
页码:1692 / 1697
页数:6
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