title: Reduction of dispersion of repolarization and prolongation of postrepolarization refractoriness explain the antiarrhythmic effects of quinidine in a model of short QT syndrome.
abstract: BACKGROUND
  Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS.
  
  
  RESULTS
  Pinacidil, an I(K-ATP) channel opener, was administered in increasing concentrations (50-100 microM) in 48 Langendorff-perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the I(Kr) blocker sotalol (100 microM) and the class I antiarrhythmic drugs flecainide (2 microM) and quinidine (0.5 microM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with sotalol and flecainide. Moreover, quinidine, in contrast to sotalol and flecainide, reduced dispersion of repolarization.
  
  
  CONCLUSIONS
  Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.
authors.affiliation: Department of Cardiology and Angiology, Hospital of the Westfälische Wilhelms-University, Münster, Germany. milbergp@uni-muenster.de
authors.forename: Peter
authors.initials: P
authors.lastname: Milberg
authors.forename: Regina
authors.initials: R
authors.lastname: Tegelkamp
authors.forename: Nani
authors.initials: N
authors.lastname: Osada
authors.forename: Rainer
authors.initials: R
authors.lastname: Schimpf
authors.forename: Christian
authors.initials: C
authors.lastname: Wolpert
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005424:Flecainide / Q000494:pharmacology; D006329:Heart Conduction System / Q000187:drug effects*; D066298:In Vitro Techniques; D020110:Pinacidil; D011802:Quinidine / Q000494:pharmacology*; D011817:Rabbits; D011897:Random Allocation; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013015:Sotalol / Q000494:pharmacology; D014665:Vasodilator Agents
chemical_list: D000889:Anti-Arrhythmia Agents; D014665:Vasodilator Agents; D020110:Pinacidil; D013015:Sotalol; D011802:Quinidine; D005424:Flecainide