The Mechanism of Pause-Induced Torsade de Pointes in Long QT Syndrome

Jinqiu Liu, M.D.; Kenneth R. Laurita, Ph.D.

Disclosures

J Cardiovasc Electrophysiol. 2005;16(9):981-987. 

In This Article

Abstract and Introduction

Introduction: Torsade de pointes (TdP), is often preceded by a short-long cycle length sequence. However, the causal relationship between the pause associated with a short-long cycle length sequence and TdP is not completely understood. This study tests the hypothesis that a pause enhances both dispersion of repolarization and EAD formation; however, EADs that form where APD is longest will be less likely to initiate TdP.
Methods and Results: We used optical mapping to measure transmural action potentials from the canine left ventricular wedge preparation. D-sotalol and ATX-II were used to mimic LQT2 and LQT3, respectively. The pause significantly enhanced mean APD (from 356 ± 20 to 381 ± 25 msec in LQT2, P < 0.05; from 609 ± 92 to 675 ± 98 msec in LQT3, P < 0.05) and transmural dispersion (from 35 ± 9 to 46 ± 11 msec in LQT2, P < 0.05; from 121 ± 85 to 171 ± 98 msec in LQT3, P < 0.05) compared to steady state pacing. Under LQT3 condition EADs, EAD-induced triggered activity, and TdP were more likely to occur following a pause. Interestingly, the triggered beat following a pause always broke through at the region of maximum local repolarization gradient.
Conclusion: These data suggest that a pause accentuates transmural repolarization gradients and facilitates the formation of EADs and EAD-induced triggered activity. In contrast to our hypothesis, the findings of this study support the concept that M-cells (where APD is longest) can play an important role in both the origination of EAD-induced triggered activity and unidirectional block associated with TdP.

Long QT syndrome (LQTS) is characterized by QT interval prolongation and sudden cardiac death caused by torsade de pointes (TdP).[1] Congenital LQTS is a disease of transmembrane ion channel proteins. Presently, mutations in seven different ion channel genes have been identified.[2] As a result of intrinsic ion channel heterogeneities across the transmural wall,[3–5] mutations of HERG (LQT2) and SCN5A (LQT3) can cause regional APD prolongation and, hence, large transmural repolarization gradients that are related to TdP.[6–10] Akar et al.[9] using optical mapping techniques in a model of LQT2 observed circular "islands" of delayed repolarization which can provide a suitable substrate for reentrant excitation. In addition to repolarization gradients, early afterdepolarizations (EADs) are also enhanced under conditions of prolonged QT interval and are believed to play a critical role in the initiation of TdP.[11] EADs have been shown to occur specifically near the endocardium from Purkinje fibers[12] or from M-cells where APD is longest.[4]

In patients, the pause associated with a short-long cycle length sequence commonly precedes the onset of TdP.[13] Importantly, a pause can increase dispersion of repolarization[8] and the formation of EADs.[14–16] Despite our knowledge of the electrophysiological substrate associated with LQTS, the causal relationship between local repolarization gradients, EADs, pauses, and TdP are not completely understood. For example, if an EAD occurs where APD is longest (i.e., where recovery is last), then where will the resulting wavefront block to initiate reentrant excitation? In addition, which is more likely to increase the occurrence of TdP, pause-enhanced EADs or pause-enhanced repolarization gradients? We hypothesize that in LQTS the pause associated with a short-long cycle length sequence enhances both dispersion of repolarization (DOR) and EAD formation; however, EADs that form where APD is longest will be less likely to initiate TdP. To test these hypotheses, high-resolution optical mapping was used to measure transmural APD, DOR, EADs, and EAD-induced triggered activity.

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