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

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 mug/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. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.