Modulation of post-pacing action potential duration and contractile responses on ventricular arrhythmogenesis in chloroquine-induced long QT syndrome

Abstract

Background: Excitation-contraction (E-C) coupling, the interaction of action potential duration (APD) and contractility, plays an essential role in arrhythmogenesis. We aimed to investigate the arrhythmogenic role of E-C coupling in the right ventricular outflow tract (RVOT) in the chloroquine-induced long QT syndrome.

Methods: Conventional microelectrodes were used to record electrical and mechanical activity simultaneously under electrical pacing (cycle lengths from 1000-100 ms) in rabbit RVOT tissue preparations before and after chloroquine with and without azithromycin. KB-R7943 (a Na⁺-Ca²⁺ exchanger [NCX] inhibitor), ranolazine (a late sodium current inhibitor), or MgSO₄ were used to assess their pharmacological responses in the chloroquine-induced long QT syndrome.

Results: Sequential infusion of chloroquine and chloroquine plus azithromycin triggered ventricular tachycardia (VT) (33.7%) after rapid pacing compared to baseline (6.7%, p = 0.004). There were greater post-pacing increases of the first occurrence of contractility (ΔContractility) in the VT group (VT vs. non-VT: 521.2 ± 50.5% vs. 306.5 ± 26.8%, p < 0.001). There was no difference in the first occurrence of action potential at 90% repolarization (ΔAPD₉₀) (VT vs. non-VT: 49.7 ± 7.4 ms vs. 51.8 ± 13.1 ms, p = 0.914). Pacing-induced VT could be suppressed to baseline levels by KB-R7943 or MgSO₄. Ranolazine did not suppress pacing-induced VT in chloroquine-treated RVOT. ΔContractility was reduced by KB-R7943 and MgSO₄, but not by ranolazine.

Conclusion: ΔContractility (but not ΔAPD) played a crucial role in the genesis of pacing-induced VT in the long QT tissue model, which can be modulated by NCX (but not late sodium current) inhibition or MgSO₄.

Keywords: Excitation-contraction coupling; Long QT; Magnesium; Na(+)-Ca(2+) exchanger inhibitor; Ranolazine; Ventricular arrhythmias.