The new selective I(Ks)-blocking agent HMR 1556 restores sinus rhythm and prevents heart failure in pigs with persistent atrial fibrillation.
BACKGROUND
Antiarrhythmic drugs for treatment of atrial fibrillation in patients with heart failure are limited by proarrhythmia and low efficacy. Experimental studies indicate that the pure I(Ks) blocking agents chromanol 293b and HMR 1556 prolong repolarization more markedly at fast than at slow heart rates and during beta-adrenergic stimulation. These properties may overcome some of the above quoted limitations.


RESULTS
Ten domestic swine underwent pacemaker implantation (PM) and atrial burst pacing to induce persistent AF. Four days after onset of persistent AF, pigs were randomized to HMR 1556 (30 mg/kg, p.o., 10 days) or placebo. All animals receiving HMR 1556 converted to SR (5.2 +/- 1.9 days), whereas placebo pigs remained in AF. Pigs treated with placebo developed high ventricular rates (297 +/- 5 bpm) and severe heart failure, whereas pigs treated with HMR 1556 remained hemodynamically stable. Left ventricular ejection fraction on the day of euthanization was significantly lower in the placebo compared to the HMR 1556 group (30 +/- 4% vs. 69 +/- 5%, p < 0.005). Similar results were seen with epinephrine levels (placebo 1563 +/- 193 pmol/l vs. HMR 613 +/-196 pmol/l, p < 0.05). Right atrial monophasic action potentials were significantly longer in the HMR 1556 compared to the placebo group (230 +/- 7 ms vs. 174 +/- 13 ms, p < 0.05).


CONCLUSIONS
The new I(Ks) blocker HMR 1556 efficiently and safely restores SR and prevents CHF in a model of persistent AF. Restoration of SR is most likely linked to a marked prolongation of atrial repolarization even at high heart rates.
Bauer
Alexander
A
Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. alexander_bauer@med.uni-heidelberg.de
Koch
Martin
M
Kraft
Patricia
P
Becker
Ruediger
R
Kelemen
Kamila
K
Voss
Frederik
F
Senges
Julia C
JC
Gerlach
Uwe
U
Katus
Hugo A
HA
Schoels
Wolfgang
W
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D002839:Chromans / Q000494:pharmacology*; D004195:Disease Models, Animal; D006329:Heart Conduction System / Q000187:drug effects*; D010138:Pacemaker, Artificial; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D012849:Sinoatrial Node; D013449:Sulfonamides / Q000494:pharmacology*; D034421:Sus scrofa
D000889:Anti-Arrhythmia Agents; D002839:Chromans; C420023:HMR 1556; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C059983:potassium channel protein I(sk)