F 16915 prevents heart failure-induced atrial fibrillation: a promising new drug as upstream therapy.
Atrial fibrillation (AF) is a common complication of heart failure. The aim of the present study was to investigate the effects of a new pure docosahexaenoic acid derivative called F 16915 in experimental models of heart failure-induced atria dysfunction. The atrial dysfunction-induced AF was investigated (1) in a dog model of tachypacing-induced congestive heart failure and (2) in a rat model of heart failure induced by occlusion of left descending coronary artery and 2 months reperfusion. F 16915 (5 g/day for 4 weeks) significantly reduced the mean duration of AF induced by burst pacing in the dog model (989 ± 111 s in the vehicle group to 79 ± 59 s with F 16915, P < 0.01). This dose of F 16915 also significantly reduced the incidence of sustained AF (5/5 dogs in the vehicle group versus 1/5 with F 16915, P < 0.05). In the rat model, the percentage of shortening fraction in the F 16915 group (100 mg/kg p.o. daily) was significantly restored after 2 months (32.6 ± 7.4 %, n = 9 vs 17.6 ± 3.4 %, n = 9 in the vehicle group, P < 0.01). F 16915 also reduced the de-phosphorylation of connexin43 from atria tissue. The present results show that treatment with F 16915 reduced the heart dilation, resynchronized the gap junction activity, and reduced the AF duration in models of heart failure. Thus, F 16915 constitutes a promising new drug as upstream therapy for the treatment of AF in patients with heart failure.
Institut de Recherche Pierre Fabre, Castres Cedex, France, bruno.le.grand@pierre-fabre.com.
Bruno
B
Le Grand
Robert
R
Letienne
Elisabeth
E
Dupont-Passelaigue
Frédérique
F
Lantoine-Adam
Frédéric
F
Longo
Monique
M
David-Dufilho
Georghia
G
Michael
Kunihiro
K
Nishida
Daniel
D
Catheline
Philippe
P
Legrand
Stéphane
S
Hatem
Stanley
S
Nattel
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D064752:Atrial Remodeling / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004285:Dogs; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000473:pathology; D008297:Male; D009540:Nicotinyl Alcohol / Q000097:blood; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; C000595231:F 16915; D011355:Prodrugs; D011725:Pyridines; D004281:Docosahexaenoic Acids; D009540:Nicotinyl Alcohol