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Journal of the American College of Cardiology
© 2006 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
QT Interval Duration
Remains a Major Risk Factor
in Long QT Syndrome Patients*
Emanuela T. Locati, MD, PHD, FESC
Perugia and Milan, Italy
Almost 50 years after the first description of congenital long
QT syndrome (LQTS), where QT interval prolongation
was recognized as the hallmark of a new pathologic entity
associated with sudden cardiac death (1), the simple linear
measurement of QT interval still stands as the strongest
independent predictor of cardiac events in LQTS patients.
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.
See page 1047
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.
AGE- AND GENDER-RELATED
DIFFERENCES OF QT INTERVAL DURATION
The variability of QT interval in serial tracings remains
largely unexplained. Its origin is probably multifactorial.
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the Division of Cardiology, Department of Clinical and Experimental
Medicine, University of Perugia, Perugia; and the “A. De Gasperis” Cardiovascular
Department, Niguarda Hospital, Milan, Italy.
Vol. 48, No. 5, 2006
ISSN 0735-1097/06/$32.00
doi:10.1016/j.jacc.2006.06.034
Age-dependent gender-related effects affect QT interval
variability. Specifically, gender differences in QTc are not
present during infancy, and QTc decreases in boys, but not
in girls, during adolescence (12,13).
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.
EFFECT OF ANTIADRENERGIC
THERAPIES ON QT INTERVAL DURATION
The QTc changes in follow-up ECGs may be due to
antiadrenergic therapies, specifically beta-blockers, largely
present in LQTS patients, particularly among those with
multiple cardiac events. The positive effect of antiadrenergic
therapies, beta-blockers and left cardiac sympathetic denervation (LCSD), on cardiac events in LQTS patients is well
documented (2,3,5,17,18), although the protective effect
may vary among genotypes (8 –10,19).
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).
1054
Locati
Editorial Comment
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.
QT INTERVAL DURATION AND LQTS GENOTYPES
In the last decade major understanding was attained of the
genetic bases of LQTS (7–10,19,21). At least 8 distinct
genetic variants have been identified (LQT1 to LQT8), and
several specific gene mutations were described within the 5
known mutant genes (KCNQ1, HERG, SCN5A, KCNE1,
and KCNE2). Approximately 40% of LQTS families have
not yet been linked to any known genes; thus, more LQTS
genes remain to be identified.
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 genotypephenotype 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
JACC Vol. 48, No. 5, 2006
September 5, 2006:1053–5
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.
CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS
The Goldenberg et al. (11) study has 2 main clinical
implications. First, the detection of QTc of ⬎500 ms at any
time during follow-up identified patients at high risk for
arrhythmic events, with the clinical implication that such
patients should receive extensive work-up and effective
treatment, beta-blockers as first choice. Second, it is necessary to obtain serial ECG tracings to better define the
individual risk, not only in symptomatic but also in asymptomatic LQTS patients.
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.
Reprint requests and correspondence: Dr. Emanuela T. Locati,
Via Vittoria Colonna 40, 20149 Milano, Italy. E-mail:
[email protected].
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