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Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice.

AbstractOBJECTIVE:
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.
AuthorsLarissa Fabritz, Paulus Kirchhof, Michael R Franz, Dieter Nuyens, Tom Rossenbacker, Alexander Ottenhof, Wilhelm Haverkamp, Günter Breithardt, Edward Carmeliet, Peter Carmeliet
JournalCardiovascular research (Cardiovasc Res) Vol. 57 Issue 4 Pg. 1085-93 (Mar 15 2003) ISSN: 0008-6363 [Print] Netherlands
PMID12650887 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Arrhythmia Agents
  • NAV1.5 Voltage-Gated Sodium Channel
  • Scn5a protein, mouse
  • Sodium Channels
  • Mexiletine
Topics
  • Action Potentials (drug effects)
  • Animals
  • Anti-Arrhythmia Agents (therapeutic use)
  • Cardiac Pacing, Artificial
  • Disease Models, Animal
  • Electrocardiography
  • Gene Deletion
  • Long QT Syndrome (complications, genetics)
  • Mexiletine (therapeutic use)
  • Mice
  • Mice, Transgenic
  • NAV1.5 Voltage-Gated Sodium Channel
  • Organ Culture Techniques
  • Sodium Channels (genetics)
  • Torsades de Pointes (etiology, prevention & control)

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