F 16915 prevents heart failure-induced atrial fibrillation: a promising new drug as upstream therapy

Naunyn Schmiedebergs Arch Pharmacol. 2014 Jul;387(7):667-77. doi: 10.1007/s00210-014-0975-3. Epub 2014 Apr 11.

Abstract

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.

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents / blood
  • Anti-Arrhythmia Agents / pharmacokinetics
  • Anti-Arrhythmia Agents / therapeutic use*
  • Atrial Fibrillation / drug therapy*
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / pathology
  • Atrial Fibrillation / physiopathology
  • Atrial Remodeling / drug effects
  • Docosahexaenoic Acids / blood
  • Docosahexaenoic Acids / metabolism
  • Docosahexaenoic Acids / pharmacokinetics
  • Docosahexaenoic Acids / therapeutic use*
  • Dogs
  • Heart Atria / metabolism
  • Heart Atria / pathology
  • Heart Failure / drug therapy*
  • Heart Failure / metabolism
  • Heart Failure / pathology
  • Heart Failure / physiopathology
  • Heart Ventricles / pathology
  • Male
  • Nicotinyl Alcohol / blood
  • Prodrugs / pharmacokinetics
  • Prodrugs / therapeutic use*
  • Pyridines / blood
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use*
  • Rats, Sprague-Dawley
  • Ventricular Remodeling / drug effects

Substances

  • Anti-Arrhythmia Agents
  • F 16915
  • Prodrugs
  • Pyridines
  • Docosahexaenoic Acids
  • Nicotinyl Alcohol