title: Acute inhibition of the Na(+)/Ca(2+) exchanger reduces proarrhythmia in an experimental model of chronic heart failure.
abstract: BACKGROUND
  Molecular remodeling in heart failure includes slowing of repolarization, leading to proarrhythmia.
  
  
  OBJECTIVE
  To evaluate the effects of Na(+)/Ca(2+) exchanger (NCX) inhibition on repolarization as a novel antiarrhythmic concept in chronic heart failure (CHF).
  
  
  RESULTS
  CHF was induced by rapid ventricular pacing in rabbits. Left ventricular function was assessed by echocardiography. Monophasic action potentials (MAPs) showed a prolongation of repolarization in CHF after atrioventricular block and stimulation at different cycle lengths. Sotalol (100 μM, n = 13) or veratridine (0.5 μM; n = 15) resulted in a further significant increase in the MAP duration. CHF was associated with an increased dispersion of repolarization, as compared with sotalol-treated (+22 ± 7 ms; P < .05) and veratridine-treated (+20 ± 6 ms; P < .05) sham hearts. In the presence of a low potassium concentration, sotalol and veratridine reproducibly induced early afterdepolarizations (EADs) and polymorphic ventricular tachyarrhythmias (VTs). SEA0400 (1 μM), a pharmacological inhibitor of NCX, significantly shortened the MAP duration (P < .01) and reduced dispersion (P < .05). It suppressed EAD in 6 of 13 sotalol-treated failing hearts and in 9 of 10 veratridine-treated failing hearts, leading to a reduction in VT (60% in sotalol-treated failing hearts and 83% in veratridine-treated failing hearts). Simulations using a mathematical model showed a reduction in the action potential duration and the number of EADs by the NCX block in all subgroups.
  
  
  CONCLUSIONS
  In an experimental model of CHF, the acute inhibition of NCX (1) reduces the MAP duration, (2) decreases dispersion of repolarization, and (3) suppresses EAD and VT. Our observations indicate for the first time that pharmacological NCX inhibition increases repolarization reserve and protects against VTs in heart failure.
authors.affiliation: Division of Clinical and Experimental Electrophysiology, Department of Cardiology and Angiology, Westfälische Wilhelms-University, University Hospital Münster, Münster, Germany. milbergp@unimuenster.de
authors.forename: Peter
authors.initials: P
authors.lastname: Milberg
authors.forename: Christian
authors.initials: C
authors.lastname: Pott
authors.forename: Gerrit
authors.initials: G
authors.lastname: Frommeyer
authors.forename: Martin
authors.initials: M
authors.lastname: Fink
authors.forename: Matthias
authors.initials: M
authors.lastname: Ruhe
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.forename: Rainer
authors.initials: R
authors.lastname: Klocke
authors.forename: Trong Hung
authors.initials: TH
authors.lastname: Quang
authors.forename: Sigrid
authors.initials: S
authors.lastname: Nikol
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Nani
authors.initials: N
authors.lastname: Osada
authors.forename: Frank U
authors.initials: FU
authors.lastname: Müller
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Dennis
authors.initials: D
authors.lastname: Noble
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy*; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D011817:Rabbits; D019831:Sodium-Calcium Exchanger / Q000187:drug effects*; D013015:Sotalol / Q000494:pharmacology*; D017180:Tachycardia, Ventricular / Q000188:drug therapy; D016171:Torsades de Pointes / Q000139:chemically induced; D014701:Veratridine / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D019831:Sodium-Calcium Exchanger; D014701:Veratridine; D013015:Sotalol; D000638:Amiodarone