title: Acceleration-induced action potential prolongation and early afterdepolarizations.
abstract: BACKGROUND
  Precipitation of torsades de pointes (TdP) has been shown to be associated with acceleration of heart rate in both experimental and clinical studies. To gain insight into the cellular mechanism(s) responsible for the initiation of acceleration-induced TdP, we studied the effect of acceleration of pacing rate in canine left ventricular epicardial, M region, endocardial, and Purkinje fiber preparations pretreated with E-4031, an IKr blocker known to induce the long QT syndrome and TdP.
  
  
  RESULTS
  Standard microelectrode techniques were used. E-4031 (1 to 2 microM) induced early after depolarization (EAD) activity in 31 of 36 M cell, 0 of 10 epicardial, 0 of 10 endocardial, and 9 of 12 Purkinje fiber preparations at basic cycle lengths (BCLs) > or = 800 msec. In 30 of 36 M cells, sudden acceleration from a BCL range of 900 to 4,000 msec to a range of 500 to 1,500 msec induced transient EAD activity if none existed before or increased the amplitude of EADs if already present. Acceleration-induced augmentation of EAD activity was far less impressive and less readily demonstrable in Purkinje fibers (4/12). In M cells, appearance of EAD activity during acceleration usually was accompanied by an abbreviation of action potential duration (APD). Within discrete ranges of rates in the physiologic range, acceleration caused a transient prolongation of APD in 38% of M cells, whether or not a distinct EAD was generated. Acceleration produced still more dramatic APD prolongation and EADs in M cells after the BCL was returned to the original slow rate. Epicardium and endocardium APD showed little change immediately after acceleration. A decrease of BCL as small as 10% and, in some cases, a single premature beat could promote EAD activity and APD prolongation in some M cells. Ryanodine (1 microM, 10/10), flunarizine (10 microM, 3/6), and low Na (97 vs 129 mM, 5/5) abolished the acceleration-induced EAD activity and APD prolongation as well as the EAD activity observed at slow rates in M cells pretreated with E-4031.
  
  
  CONCLUSIONS
  Our results suggest that acceleration from an initially slow rate or a single premature beat can induce or facilitate transient EAD activity and APD prolongation in canine ventricular M cell preparations pretreated with an IKr blocker via a mechanism linked to intracellular calcium loading. Our data provide evidence in support of an important contribution of electrogenic Na/Ca exchange current to this process. These acceleration-induced changes can result in the development of triggered activity as well as a marked dispersion of repolarization in ventricular myocardium and, thus, may contribute to the precipitation of TdP in patients with the congenital (HERG defect) and acquired (drug-induced) long QT syndrome.
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York 13501, USA.
authors.forename: A
authors.initials: A
authors.lastname: Burashnikov
authors.forename: C
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004699:Endocardium / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005444:Flunarizine / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008564:Membrane Potentials; D008839:Microelectrodes; D010496:Pericardium / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D016171:Torsades de Pointes / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D005444:Flunarizine