title: Antiarrhythmic effects of free polyunsaturated fatty acids in an experimental model of LQT2 and LQT3 due to suppression of early afterdepolarizations and reduction of spatial and temporal dispersion of repolarization.
abstract: BACKGROUND
  Torsades de pointes (TdP) are induced by early afterdepolarizations (EADs) in the presence of an increased dispersion of repolarization. Free polyunsaturated fatty acids (PUFAs) have been suggested to influence cardiac repolarization.
  
  
  OBJECTIVE
  The purpose of this experimental study was to investigate the electrophysiologic effects of PUFAs in a model of LQT2 and LQT3.
  
  
  METHODS
  We investigated the acute antiarrhythmic potential of α-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) in a whole-heart model of long QT2 (LQT2) and long QT3 (LQT3) syndrome.
  
  
  RESULTS
  In 123 Langendorff-perfused rabbit hearts, the I(Kr)-blocking drug erythromycin (E; 300 μM) or veratridine (V; 0.5 μM), an inhibitor of sodium channel inactivation, significantly increased monophasic ventricular action potentials (MAPs), thereby mimicking LQT2 and LQT3 syndrome. In atrioventricular-blocked hearts, 8 epicardial and endocardial MAPs demonstrated a significant increase in spatial and temporal dispersion. After lowering potassium concentration, E led to EADs and TdP in 44 and 41 of 53 hearts, respectively. Pretreatment with V led to EAD (TdP) in 39 (32) of 43 hearts. Additional treatment with ALA, DHA, or EPA (10 to 20 μM) in the LQT2 model, randomly assigned to 3 groups, suppressed EAD in 72% of ALA-treated hearts and in all hearts that were treated with EPA or DHA. This led to a reduction of TdP of 67% (ALA) and to complete abolishment of TdP in all hearts that were treated with EPA or DHA. A comparable finding was seen in V-pretreated hearts. In addition, DHA and EPA significantly shortened MAP duration and reduced spatial and temporal dispersion of repolarization (P <.01).
  
  
  CONCLUSIONS
  The present study showed for the first time that PUFAs are effective in preventing TdP in an experimental model of LQT2 and LQT3 syndrome due to a reversion of AP prolongation, a reduction of spatial and temporal dispersion of repolarization and a suppression of EAD. The PUFA effect is stronger in LQT2 than in LQT3 syndrome, and the antitorsadogenic effect is more remarkable with DHA and EPA as compared with ALA.
authors: Hospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology, Division of Experimental and Clinical Electrophysiology, Münster, Germany. milbergp@uni-muenster.de
authors: Peter
authors: P
authors: Milberg
authors: Gerrit
authors: G
authors: Frommeyer
authors: Anne
authors: A
authors: Kleideiter
authors: Alicia
authors: A
authors: Fischer
authors: Nani
authors: N
authors: Osada
authors: Günter
authors: G
authors: Breithardt
authors: Michael
authors: M
authors: Fehr
authors: Lars
authors: L
authors: Eckardt
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D011817:Rabbits; D016171:Torsades de Pointes / Q000188:drug therapy* / Q000503:physiopathology; D017962:alpha-Linolenic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D005231:Fatty Acids, Unsaturated; D017962:alpha-Linolenic Acid; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid