title: Cytosolic calcium accumulation and delayed repolarization associated with ventricular arrhythmias in a guinea pig model of Andersen-Tawil syndrome.
abstract: BACKGROUND
  Andersen-Tawil syndrome (ATS1)-associated ventricular arrhythmias are initiated by frequent, hypokalemia-exacerbated, triggered activity. Previous ex vivo studies in drug-induced Andersen-Tawil syndrome (DI-ATS1) models have proposed that arrhythmia propensity in DI-ATS1 derives from cytosolic Ca(2+) ([Ca(2+)](i)) accumulation leading to increased triggered activity.
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that elevated [Ca(2+)](i) with concomitant APD prolongation, rather than APD dispersion, underlies arrhythmia propensity during DI-ATS1.
  
  
  METHODS
  DI-ATS1 was induced in isolated guinea pig ventricles by perfusion of 2 mM KCl Tyrode solution containing 10 μM BaCl(2). APD and [Ca(2+)](i) from the anterior epicardium were quantified by ratiometric optical voltage (di-4-ANEPPS) or Ca(2+) (Indo-1) mapping during right ventricular pacing with or without the ATP-sensitive potassium channel opener pinacidil (15 μM).
  
  
  RESULTS
  APD gradients under all conditions were insufficient for arrhythmia induction by programmed stimulation. However, 38% of DI-ATS1 preparations experienced ventricular tachycardias (VTs), and all preparations experienced a high incidence of premature ventricular complexes (PVCs). Pinacidil decreased APD and APD dispersion and reduced VTs (to 6%), and PVC frequency (by 79.5%). However, PVC frequency remained significantly greater relative to control (0.5% ± 0.3% of DI-ATS1). Importantly, increased arrhythmia propensity during DI-ATS1 was associated with diastolic [Ca(2+)](i) accumulation and increased [Ca(2+)](i) transient amplitudes. Pinacidil partially attenuated the former but did not alter the latter.
  
  
  CONCLUSIONS
  The study data suggest that arrhythmias during DI-ATS1 may be a result of triggered activity secondary to prolonged APD and altered [Ca(2+)](i) cycling and less likely dependent on large epicardial APD gradients forming the substrate for reentry. Therefore, therapies aimed at reducing [Ca(2+)](i) rather than APD gradients may prove effective in treatment of ATS1.
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112-5000, USA.
authors.forename: Przemysław B
authors.initials: PB
authors.lastname: Radwański
authors.forename: Rengasayee
authors.initials: R
authors.lastname: Veeraraghavan
authors.forename: Steven
authors.initials: S
authors.lastname: Poelzing
mesh_terms: D000200:Action Potentials; D050030:Andersen Syndrome / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D002304:Cardiac Pacing, Artificial; D003600:Cytosol / Q000378:metabolism*; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D010496:Pericardium / Q000166:cytology / Q000378:metabolism*; D020110:Pinacidil / Q000494:pharmacology; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D049990:Membrane Transport Modulators; D020110:Pinacidil; D002118:Calcium