T-wave morphology abnormalities in benign, potent, and arrhythmogenic I(kr) inhibition

Abstract

Background: There is a consensus on the limited value of the QTc interval prolongation as a surrogate marker of drug cardiotoxicity and as a risk stratifier in inherited long QT syndrome (LQTS) patients.

Objective: We investigated the interest of repolarization morphology in the acquired and the inherited LQTS.

Methods: We analyzed 2 retrospective electrocardiographic (ECG) datasets from healthy on/off moxifloxacin and from genotyped KCNH2 patients. We measured QT, RR, and T-peak to T-end intervals, early repolarization duration (ERD) and late repolarization duration, T-roundness, T-amplitude, left (αL) and right slopes of T-waves. We designed multivariate logistic models to predict the presence of the KCNH2 mutation or moxifloxacin while adjusting for the level of QTc prolongation and the level of heart rate in LQT2 patients. Independent learning and validation sets were used. A list of 4,874 ECGs from 411 healthy individuals, 293 from 143 LQT2 carriers and 150 noncarrier family members were analyzed.

Results: In the moxifloxacin model, ERD was associated with the presence of the drug (odds ratio = 1.15 per ms increase, confidence interval 1.04 to 1.26, P = .0001) after adjustment for QTc. The model for the LQT2 revealed that left slope was associated with the presence of the KCNH2 mutation (odds ratio = 0.38 per 1.5 μV/ms decrease, confidence interval 0.23 to 0.64, P = .0002). Only T-roundness complemented QTc in the model investigating cardiac events in LQT2.

Conclusions: These observations demonstrate that the phenotypic expression of KCNH2 mutations and the effect of IKr-inhibitory drug on the surface electrocardiogram are specific. Future research should investigate whether this phenomenon is linked to different level/form of loss functions of Ikr channels, and whether they could result in different arrhythmogenic mechanisms.

Conflict of interest statement

Conflict of Interest: Drs. Couderc and Zareba have financial interest in a private company which licensed part of the technology described in this manuscript.

Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Panel A illustrates the measurements on the T-waves from lead II and from first eigenlead (ev1). Panel B represents the T-loop i.e. T-wave signals plotted along ev1 and ev2 leads in the upper panel, and the eigenlead 1 (ev1) in the lower panel. ERD30% intervals originate from the time of maximum vector amplitude (Vmax) and ends at the time when Vmax has reached 30% decrease in amplitude (demarcated by the bold arc labeled “30% Vmax threshold”).

Figure 2

Schematic description of the processes involved in the digitization of the paper ECG tracings from LQT2 families.

Figure 3

Receiver operating characteristic curves for the discrimination of carriers from non-carrier LQT2 patients using 3 logistic models. The left panel shows the limited benefit of considering αL in addition to RR and QTc in LQT2 patients with prolong QTc. The right panel revealed that abnormal morphology is associated with major discriminative power when considering LQT2 patients with normal QTc interval.

Figure 4

Kaplan-Meier curves describing the probability of cardiac events in LQT2 patients based on T roundness. Panel A: all population; panel B: LQT2 carriers with QTc≥500 msec and panel C: LQT2 carriers with QTc