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

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 chloroquineinduced 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 (AContractility) 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 (AAPD90) (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. AContractility was reduced by KB-R7943 and MgSO4, but not by ranolazine. Conclusion: AContractility (but not AAPD) 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.

Automated summary

This study aimed to investigate the arrhythmogenic role of excitation-contraction coupling in the right ventricular outflow tract in chloroquine-induced long QT syndrome. The results showed that sequential infusion of chloroquine and azithromycin triggered ventricular tachycardia, which could be suppressed by NCX inhibitors or MgSO4.