title: Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice.
abstract: OBJECTIVE
  It has been suggested that both pacing and treatment with mexiletine may reduce torsade de pointes (TdP) arrhythmias in patients with long QT syndrome 3 (LQT3), but it is not fully understood how these interventions could prevent TdP. We therefore studied the effects of pacing and mexiletine in mice with a heterozygous knock-in DeltaKPQ SCN5A(Delta/+) deletion (SCN5A-Tg), a murine LQT3 model.
  
  
  METHODS
  Three right and left ventricular monophasic action potentials (MAPs) were simultaneously recorded in Langendorff-perfused hearts of SCN5A-Tg and wild type (WT) littermates. AV block was induced, and pacing was performed at baseline and during mexiletine infusion (4 microg/ml). MAP recordings were analysed for action potential duration (APD), APD dispersion, and early afterdepolarisations (EADs) and related to spontaneous arrhythmias.
  
  
  RESULTS
  After inducing AV block, SCN5A-Tg hearts were bradycardic [SCN5A-Tg 532+/-60 vs. WT 284+/-48 ms cycle length (CL, mean+/-S.E.M., P<0.05(*))]. EADs occurred in 16/18, and polymorphic ventricular tachycardia (pVT) in 11/18 SCN5A-Tg but not in 19 WT. SCN5A-Tg had longer APD than WT hearts*. At CL of 200 ms and longer, APD dispersion was higher in SCN5A-Tg [dispersion (APD70): 12+/-3 ms vs. 5+/-2 ms at CL=200 ms*], and increased to 35+/-4 ms* directly prior to pVT episodes. Sudden rate accelerations initially increased APD dispersion due to EADs and APD alternans in SCN5A-Tg, but pacing then reduced APD dispersion. Pacing suppressed (n=9/9) and prevented (n=49/50) pVT. Mexiletine shortened APD at long CL*, and suppressed pVT (n=4/5*), but did not prevent pVT during normal rhythm.
  
  
  CONCLUSIONS
  Bradycardia, increased dispersion of APD and EADs provoke ventricular ectopy and pVT in SCN5A-Tg hearts. Ventricular pacing reduces APD dispersion, suppresses EADs and prevents pVT in SCN5A-Tg hearts. These effects provide a pathophysiological rationale for pacing in LQT3.
authors.affiliation: Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany. fabritzl@uni-muenster.de <fabritzl@uni-muenster.de>
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
authors.forename: Michael R
authors.initials: MR
authors.lastname: Franz
authors.forename: Dieter
authors.initials: D
authors.lastname: Nuyens
authors.forename: Tom
authors.initials: T
authors.lastname: Rossenbacker
authors.forename: Alexander
authors.initials: A
authors.lastname: Ottenhof
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haverkamp
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Edward
authors.initials: E
authors.lastname: Carmeliet
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004562:Electrocardiography; D017353:Gene Deletion; D008133:Long QT Syndrome / Q000150:complications* / Q000235:genetics; D008801:Mexiletine / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009924:Organ Culture Techniques; D015222:Sodium Channels / Q000235:genetics; D016171:Torsades de Pointes / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D008801:Mexiletine