Priori SG, Napolitano C, Schwartz PJ, Grillo M, Bloise R, Ronchetti E, Moncalvo C, Tulipani C, Veia A, Bottelli G, Nastoli J. Association of Long QT Syndrome Loci and Cardiac Events Among Patients Treated With β-Blockers. JAMA. 2004;292(11):1341-1344. doi:10.1001/jama.292.11.1341
Author Affiliations: Molecular Cardiology, IRCCS Fondazione Maugeri (Drs Priori, Napolitano, Grillo, Bloise, Ronchetti, Moncalvo, Tulipani, and Veia and Mss Bottelli and Nastoli); Department of Cardiology, IRCCS Policlinico S. Matteo (Dr Schwartz); and University of Pavia (Drs Priori and Schwartz), Pavia, Italy.
Context Data on the efficacy of β-blockers in the 3 most common genetic
long QT syndrome (LQTS) loci are limited.
Objective To describe and assess outcome in a large systematically genotyped population
of β-blocker–treated LQTS patients.
Design, Setting, and Patients Consecutive LQTS-genotyped patients (n = 335) in Italy treated with β-blockers
for an average of 5 years.
Main Outcome Measures Cardiac events (syncope, ventricular tachycardia/torsades de pointes,
cardiac arrest, and sudden cardiac death) while patients received β-blocker
therapy according to genotype.
Results Cardiac events among patients receiving β-blocker therapy occurred
in 19 of 187 (10%) LQT1 patients, 27 of 120 (23%) LQT2 patients, and 9 of 28 (32%) LQT3 patients (P<.001). The risk of cardiac
events was higher among LQT2 (adjusted relative risk,
2.81; 95% confidence interval [CI], 1.50-5.27; P =
.001) and LQT3 (adjusted relative risk, 4.00; 95%
CI, 2.45-8.03; P<.001) patients than among LQT1 patients, suggesting inadequate protection from β-blocker
therapy. Other important predictors of risk were a QT interval corrected for
heart rate that was more than 500 ms in patients receiving therapy (adjusted
relative risk, 2.01; 95% CI, 1.16-3.51; P = .01)
and occurrence of a first cardiac event before the age of 7 years (adjusted
RR, 4.34; 95% CI, 2.35-8.03; P<.001).
Conclusion Among patients with genetic LQTS treated with β-blockers, there
is a high rate of cardiac events, particularly among patients with LQT2 and LQT3 genotypes.
Long QT syndrome (LQTS) is a genetic disease characterized by prolonged
ventricular repolarization, syncope, ventricular arrhythmias, and sudden death,1- 3 often precipitated by
emotion or exercise. Primarily according to nonrandomized trial evidence, β-blockers
are considered first-line prophylactic therapy,4 whereas
patients refractory to β-blockers may be treated with left-sided cardiac
sympathetic denervation, pacemakers, or implantable cardioverter defibrillators.1,5- 8 The
hypothesis that the efficacy of therapy may vary according to the genetic
form of the disease has been proposed7 but
not thoroughly investigated.
Three genetic loci account for nearly 98% of genetically characterized
patients. In this investigation, we sought to describe and assess outcomes
of β-blocker–treated patients affected by the 3 most common genetic
loci of LQTS9: LQT1, LQT2, and LQT3, caused by genetic
defects on KCNQ1, KCNH2,
and SCN5A genes.
The study population included 335 genotyped LQT1, LQT2, or LQT3 patients treated
with long-term β-blocker therapy. For each patient, data on personal
and family history, cardiac events, and therapy were systematically recorded
at each visit or medical contact. The specific β-blocker used, as well
as dose, was at the discretion of the treating physician. LQTS-related cardiac
events included unexplained syncope, torsades de pointes, ventricular tachycardia,
aborted cardiac arrest, and sudden cardiac death. All patients or their guardians
provided written informed consent for clinical and genetic evaluation. The
protocol was approved by the institutional review board of the Policlinico
S. Matteo and of the Maugeri Foundation, Pavia, Italy.
Patients were consecutively genotyped at the Molecular Cardiology Laboratories
of the Maugeri Foundation as carriers of a single mutation on KCNQ1, KCNH2, or SCN5A genes;
carriers of double mutations, representing on average 3% to 5% of the patients,
were excluded from the study.
DNA was extracted from peripheral blood lymphocytes and amplified with
primer pairs for KCNQ1, KCNH2,
and SCN5A. Genetic analysis was performed by standard
methods: denaturating high-performance liquid chromatography (Wave Transgenomics,
Omaha, Neb) was performed on polymerase chain reaction–amplified DNA,
encompassing the entire open reading frame of each gene, by using intronic
primers. When abnormal chromatograms were identified, double-strand sequencing
of amplified genomic DNA (ABI Prism 310; Applied Biosystems, Foster City,
Calif) of the corresponding amplicon was performed. In addition to the previously
reported polymorphisms, all DNA variants causing coding variations and occurring
in more than 1 in 100 of the control population (400 healthy controls; ie,
800 alleles) were considered polymorphisms.
All analyses were performed with the SPSS 11.0 statistical package (SPSS
Inc, Chicago, Ill). Statistical significance was set at P≤.05. Genetic loci–related differences for continuous variables
were assessed by using 1-way analysis of variance, with post hoc analysis
with the Tukey test, whereas differences for categorical variables were assessed
with the Pearson χ2 test. Survival analyses included construction
of Kaplan-Meier plots with comparisons with the log-rank χ2 test,
as well as forward-selection Cox proportional hazards modeling. We considered
sex, QT interval corrected for heart rate (QTc), occurrence of cardiac events
before therapy, age at first cardiac event before therapy, family history
of sudden death, and genotype as candidate variables.
The 335 genotyped LQTS patients were from 187 families with mutations
on KCNQ1 (LQT1; n = 187), KCNH2 (LQT2; n = 120), or SCN5A (LQT3; n = 28) genes treated
with β-blockers. Before therapy, 159 of 335 (47%) experienced cardiac
events. The mean (SD) age at initiation of β-blocker therapy was 21 (17)
years (interquartile range, 8.5-31.7 years); the median follow-up for patients
without events and receiving β-blocker therapy was 4.7 years (range,
0.6-36 years). As summarized in Table 1, no differences among LQT1, LQT2, and LQT3 patients were observed in age,
age at initiation of therapy, observation time while receiving β-blockers,
and age at first cardiac event before therapy. However, LQT1 patients had a shorter QTc interval. Data for type of β-blocker
and dosage per kilogram of body weight were available for 266 individuals:
69% of them were treated with either propranolol (average daily dose, 2.2
[SD, 1.04] mg/kg) or nadolol (average daily dose, 1.2 [SD, 0.5] mg/kg ); there
were no dosage differences among the 3 genotypes (P =
There were 55 patients (16%) who experienced cardiac events while receiving β-blocker
therapy, of whom 14 (25%) had a cardiac arrest; 4 sudden cardiac deaths occurred
(1 LQT1 and 3 LQT3). Events
were not evenly distributed in the 3 loci, with LQT1 having
the lowest incidence of cardiac events (LQT1: 19/187
[10%]; LQT2: 27/120 [23%]; and LQT3: 9/28 [32%]; P = .001) (Table 1 and Figure 1).
In a multivariable model, important predictors of time free of events
were first cardiac event before therapy in early childhood (age ≤7 years),
QTc more than 500 ms in patients receiving therapy, and genetic locus other
than LQT1 (Table
2). When we combined patients with LQT2 and LQT3, they were at substantially increased risk for cardiac
events compared with those with LQT1 (18/187 [10%]
vs 36/148 [24%]; odds ratio, 2.8; 95% confidence interval [CI], 1.6-5.2; P<.001). Similarly, LQT2 and LQT3 patients were at increased risk for cardiac arrest
or sudden cardiac death compared with those with LQT1 (8%
vs 1%; odds ratio, 8.1; 95% CI, 1.8-37; P = .001).
Four of 14 patients experiencing cardiac arrest while receiving therapy had
been asymptomatic before therapy; thus, cardiac arrest was their first symptom
These results were confirmed in a supplementary analysis of the 187
probands of each family to correct for a possible confounding effect introduced
by the presence of family members. In another supplementary analysis, we found
that LQT2 or LQT3 genotype
was associated with a higher risk of cardiac events in patients receiving β-blockers,
even after excluding patients who had a cardiac arrest before therapy (49
events: 2/183 LQT1, 7/110 LQT2, and 3/23 LQT3; odds ratio, 2.15; 95% CI,
1.2-4.2; P = .002).
Prophylactic therapy with β-blockers is the mainstay treatment
for LQTS patients. In our large series, however, we found a high rate of cardiac
events in patients receiving β-blocker therapy, particularly for patients
with LQT2 and LQT3 genotypes.
These observations are troubling and suggest that, for some patients, genotyping
may be useful for identifying candidates for more aggressive interventions,
possibly including defibrillator implantation.
Our findings are consistent with existing evidence that genetic background
may influence the severity of the disease and its clinical manifestations
before treatment.10 In 1985, Schwartz4 provided the first data indicating that a subset of
LQTS patients was not fully protected by β-blockers. In 2000, Moss et
al7 further quantified this worrisome phenomenon
and, reporting data on 139 genotyped patients, introduced the concept that
the response to β-blockers may be modulated by genetic substrate. We
have extended those observations by showing in a large systematically genotyped β-blocker–treated
cohort a gradient of risk from LQT1 to LQT2 to LQT3 genotypes. Furthermore, we have
shown that in addition to genotype, other important predictors of cardiac
events in patients receiving therapy include QTc interval and younger age
at a first pretherapy cardiac event.
Because no randomized trial data exist, our findings about the value
of defibrillator implantation in β-blocker–treated LQTS patients
who have not experienced a cardiac arrest cannot be considered conclusive.
Nonetheless, these findings suggest that prophylactic defibrillator therapy
may be a reasonable addition to β-blockers in patients with LQT2 or LQT3 genotypes. However, a decision
to implant a defibrillator in LQT2 and LQT3 patients in the absence of definitive randomized trial evidence
is a complex one that requires consideration of important issues such as the
implantable cardioverter defibrillator's impact on quality of life of young
patients, high complication rates, the acceptance of the device by patients
and their families as an alternative, and the incomplete but additional protection
by left-sided cardiac sympathetic stimulation.5 Furthermore,
it is unlikely that β-blocker therapy could be safely discontinued after
This study is based on an observational registry and is subject to all
the inherent limitations of such an analysis. Because LQTS is a relatively
rare disease, it is unlikely that large-scale randomized trial data will become
available soon, meaning that evaluation and treatment of these patients must
occur in a setting of incomplete evidence. Furthermore, approximately 40%
of LQTS patients cannot be genotyped on the known loci, so for these patients, β-blockers
remain the recommended therapy.