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J Am Coll Cardiol, 2006; 48:1053-1055, doi:10.1016/j.jacc.2006.06.034
(Published online 6 July 2006). © 2006 by the American College of Cardiology Foundation |
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Division of Cardiology, Department of Clinical and Experimental Medicine, University of Perugia, Perugia; and the "A. De Gasperis" Cardiovascular Department, Niguarda Hospital, Milan, Italy.
* Reprint requests and correspondence: Dr. Emanuela T. Locati, Via Vittoria Colonna 40, 20149 Milano, Italy. (Email: emlocati{at}fastwebnet.it).
Prolonged corrected QT interval (QTc) was a powerful independent risk factor for cardiac event (syncope or cardiac arrest) since the initial analysis of patients enrolled in the International LQTS Registry (2–3). Subsequent analyses confirmed that finding (4–10). Incremental changes of QT interval carried higher risk for sudden death, and a cutoff of QTc >500 ms consistently identified higher-risk patients.
Most analyses of the International LQTS Registry were based on QT interval measured on the first available electrocardiogram (ECG) (6–8). This was done to avoid possible selection bias, because symptomatic patients tended to have more ECG recordings than asymptomatic subjects, and to limit possible effects of concomitant therapies, which were less likely to be present in the earliest ECG.
The study by Goldenberg et al. (11) in this issue of the Journal first evaluated possible incremental benefit of follow-up ECG on risk stratification. Its main results were that maximum QTc, rather than baseline QTc, was better correlated with risk of cardiac events during follow-up and that an increased number of ECG tracings may improve risk stratification. The major clinical implications are that serial ECG tracings should be routinely obtained during clinical follow-up of LQTS patients and that changes of QT interval duration may be monitored to evaluate the effect of therapies in LQTS patients.
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Age- and gender-related differences of QT interval duration |
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 Top Age- and gender-related... Effect of antiadrenergic...QT interval duration and...Clinical implications and future...References |
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The present study could not determine the effect of time-dependent QTc changes during adolescence on risk of cardiac events. However, previous studies suggested that cardiac events may decrease in LQTS boys after puberty in parallel with decreased QT duration, although LQTS girls remained at higher risk of cardiac events even in adult life (6–8).
Normal adult women have longer QT intervals than men; the normal cut-off for QTc interval is 440 ms for men and 460 ms for women (14). As to heart rate dependence of the QT interval, adult women have longer QT intervals at longer cycle lengths than men (15).
Higher female prevalence was observed in torsade de pointes associated with acquired prolonged repolarization, regardless of agents provoking QT prolongation. Recurrent self-terminating torsade de pointes may be more frequent among women than men, owing to unknown gender differences in electrophysiologic substrate (16).
These phenomena may account for the apparent gender imbalance steadily observed among patients referred to the International LQTS Registry (2,3,6–8). Diagnosis of LQTS may be more likely in women, with later onset of repetitive nonfatal events, whereas LQTS may remain undetected in men, with earlier and more often fatal events. Thus, need for treatment may vary in men and women according to age- and gender-dependent changes in QT interval duration.
Age- and gender-dependent QTc cut-off should be used for LQTS diagnosis, particularly among adults, and QTc should be evaluated as a time-dependent risk factor in LQTS patients.
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Effect of antiadrenergic therapies on QT interval duration |
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TopAge- and gender-related...Effect of antiadrenergic...QT interval duration and...Clinical implications and future...References |
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Scant data are available on the effects of antiadrenergic therapies on QT interval duration. Beta-blockers have limited effect on normal QT interval, but the effect may be larger in LQTS patients, with possible differences among genotypes. A QT interval shortening was observed after LCSD, where patients with significant QTc shortening (QTc <500 ms) after LCSD had lower risk of recurrent cardiac events (18).
A QT interval shortening may indicate decreased heterogeneity in ventricular repolarization, becoming less vulnerable to cardiac arrhythmias, such as torsade de pointes, probably initiated by early after-depolarization–induced activity (20).
The present study by Goldenberg et al. (11) observed correlation between QT interval shortening and beneficial effect of antiadrenergic therapies, particularly beta-blockers. A significant QTc shortening during antiadrenergic therapy, and specifically QTc <500 ms, could be viewed as a positive finding during clinical follow-up. However, this should be confirmed by studies specifically evaluating the long-term effect of therapies on QT interval.
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QT interval duration and LQTS genotypes |
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TopAge- and gender-related...Effect of antiadrenergic...QT interval duration and...Clinical implications and future...References |
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The LQTS genes encode ion channel subunits involved in the repolarization phase of the cardiac action potential. Most known genotypes are associated with impaired function of cardiac K+ channels regulating outward K+ currents active during late ventricular repolarization, whereas the rare and highly malignant variant LQT3 has impaired function of cardiac Na+ channels, with late persistent inward currents delaying ventricular repolarization (21).
Genotypes may influence the clinical course of LQTS (6–10,19). Gene-specific triggers for life-threatening arrhythmias have been described (9), but the genotype-phenotype correlation is not univocal, owing to different penetrance of LQTS genes (22) and to variable expression of different gene mutations among LQTS gene carriers (23).
The extent of QT interval prolongation varies among LQTS genotypes, with LQT3 patients having the most pronounced QT prolongation (7,8). Besides linear QT interval measurements, typical morphologic abnormalities of ventricular repolarization also have been described in LQTS, and specific T-wave patterns have been associated with distinct genotypes (24).
Selective effects of antiarrhythmic therapies according to genotype were also shown in pilot studies. Patients with LQT3 may benefit from Na+ channel blockers, mexiletine or flecainide, or from cardiac pacing, being at higher risk of arrhythmia at slow heart rates (25,26). These first attempts for gene-specific therapy are promising, although beneficial long-term effects of such therapies are not demonstrated yet.
Gene-specific differences in rate dependency of QT duration also have been described (9,25,27). Preliminary findings indicated that LQT1 and LQT2 patients, with K+ channel abnormalities, have impaired shortening of QT duration at fast heart rate. In contrast, LQT3 patients, with impaired inactivation of cardiac Na+ channels, have further QT prolongation at longer cardiac cycles (9,25). Preliminary findings also indicated that distinct patterns of circadian QT variability are present in different LQTS genotypes. Patients with the LQT3 genotype, with further QT prolongation at low heart rate, have longer QTc duration during sleep and increased incidence of cardiac events during sleep and at rest (9,27). In contrast, LQT1 and LQT2 patients appear to have longer QTc during the day, consistent with impaired shortening of QT duration at fast heart rate, and higher incidence of cardiac events during activity or stress (9,27).
Differences in QT interval variability among genotypes remain to be confirmed in a larger series of LQTS patients before they can be introduced in the clinical risk stratification of LQTS patients.
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Clinical implications and future directions |
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TopAge- and gender-related...Effect of antiadrenergic...QT interval duration and...Clinical implications and future...References |
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More accurate age- and gender-dependent cut-off for QTc interval among adults and evaluation of possible beneficial effects of concurrent therapies on QTc duration should further improve the clinical management of LQTS patients.
Other parameters measuring ventricular repolarization besides linear QT interval, such as heart rate dependence of QT interval, morphologic characteristic of T-wave morphology, or T-wave alternans, could contribute to better risk stratification. Improved genotype-phenotype correlations, with identification of gene-specific effects of different therapies on QT interval prolongation may lead to gene-specific therapies in LQTS patients.
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Footnotes |
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References |
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TopAge- and gender-related...Effect of antiadrenergic...QT interval duration and...Clinical implications and future...References |
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This article has been cited by other articles:
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  S. P. Etheridge, S. Sanatani, M. I. Cohen, C. A. Albaro, E. V. Saarel, and D. J. Bradley Long QT Syndrome in Children in the Era of Implantable Defibrillators J. Am. Coll. Cardiol., October 2, 2007; 50(14): 1335 - 1340. [Abstract] [Full Text] [PDF]
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