Inhibition of I(f) in the atrioventricular node as a mechanism for dronedarone's reduction in ventricular rate during atrial fibrillation.
BACKGROUND
In clinical trials, dronedarone lowers ventricular rate during atrial fibrillation (AF). This agent was recently demonstrated to inhibit If in the sinoatrial node.


OBJECTIVE
The purpose of this study was to examine whether dronedarone inhibits If 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 If 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.


CONCLUSIONS
Dronedarone, which is concentrated in myocardial tissue, reduces ventricular rate during AF by slowing AV conduction. Absence of this effect after ivabradine administration implicates If inhibition as a mechanism.
Beth Israel Deaconess Medical Center and; Harvard Medical School, Boston, Massachusetts. Electronic address: rverrier@bidmc.harvard.edu.
Richard L
RL
Verrier
Marcel F
MF
Sobrado
Vitor P F
VP
Pagotto
Alexandre F
AF
Kanas
Ananda D
AD
Machado
Bruno B
BB
Varone
Lucas F
LF
Sobrado
Bruce D
BD
Nearing
Dewan
D
Zeng
Luiz
L
Belardinelli
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001283:Atrioventricular Node / Q000187:drug effects / Q000503:physiopathology*; D001552:Benzazepines / Q000493:pharmacokinetics; D054815:Cyclic Nucleotide-Gated Cation Channels; D004195:Disease Models, Animal; D000077764:Dronedarone; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D000077550:Ivabradine; D008297:Male; D013552:Swine; D016277:Ventricular Function, Left / Q000187:drug effects*
D001552:Benzazepines; D054815:Cyclic Nucleotide-Gated Cation Channels; D000077550:Ivabradine; D000077764:Dronedarone; D000638:Amiodarone
A-H; ACh; AERP; AF; AV; Atrial fibrillation; Atrioventricular node; Dronedarone; ECG; Human hyperpolarization-activated cyclic nucleotide-gated (HCN) channel; I(f) inhibition; IV; Ivabradine; MAP; RA; VERP; acetylcholine; atrial effective refractory period; atrial fibrillation; atrial-His; atrioventricular; electrocardiogram; hHCN4; human hyperpolarization-activated cyclic nucleotide-gated channel 4; intravenous; mean arterial pressure; right atrial; ventricular effective refractory period