title: Cellular basis for the electrocardiographic and arrhythmic manifestations of Timothy syndrome: effects of ranolazine.
abstract: BACKGROUND
  Timothy syndrome is a multisystem disorder associated with QT interval prolongation and ventricular cardiac arrhythmias. The syndrome has been linked to mutations in Ca(V)1.2 resulting in gain of function of the L-type calcium current (I(Ca,L)). Ranolazine is an antianginal agent shown to exert an antiarrhythmic effect in experimental models of long QT syndrome.
  
  
  OBJECTIVE
  The purpose of this study was to develop and characterize an experimental model of Timothy syndrome by using BayK8644 to mimic the gain of function of I(Ca,L) and to examine the effects of ranolazine.
  
  
  METHODS
  Action potentials from epicardial and M regions and a pseudo-electrocardiogram (ECG) were simultaneously recorded from coronary-perfused left ventricular wedge preparations, before and after addition of BayK8644 (1 microM).
  
  
  RESULTS
  BayK8644 preferentially prolonged action potential duration of the M cell, leading to prolongation of the QT interval and an increase in transmural dispersion of repolarization (from 44.3 +/- 7 ms to 86.5 +/- 25 ms). Stimulation at cycle lengths of 250-500 ms led to ST-T wave alternans due to alternation of the plateau voltage of the M cell action potential as well as development of delayed afterdepolarizations in epicardial and M cell action potentials. Ventricular extrasystoles and tachycardia (monomorphic, bidirectional, or torsades de pointes) developed spontaneously or after rapid pacing. Peak and late I(Na) were unaffected by BayK8644. Clinically relevant concentrations of ranolazine (10 microM) suppressed all actions of BayK8644.
  
  
  CONCLUSIONS
  A left ventricular wedge model of long QT syndrome created by augmentation of I(Ca,L) recapitulates the ECG and arrhythmic manifestations of Timothy syndrome, which can be suppressed by ranolazine.
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York 13501-1787, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Sicouri
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Timothy
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Zygmunt
authors.forename: Aaron
authors.initials: A
authors.lastname: Glass
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Goodrow
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000009:adverse effects; D000083:Acetanilides / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000009:adverse effects; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography; D004699:Endocardium / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D016171:Torsades de Pointes / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D018879:Ventricular Premature Complexes / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D002120:Calcium Channel Agonists; D004791:Enzyme Inhibitors; D010879:Piperazines; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000069458:Ranolazine