Risk Factors for Aborted Cardiac Arrest and Sudden Cardiac Death in Children with the Congenital Long-QT Syndrome

Abstract

Background

The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death (SCD) in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified

Methods and Results

Cox proportional hazards regression modeling was used to identify risk factors for aborted cardiac arrest (ACA) or SCD in 3,015 LQTS children from the International LQTS Registry who were followed up from age 1 through 12 years. The cumulative probability of the combined end point was significantly higher in males (5%) than in females (1%; p<0.001). Risk factors for ACA or SCD during childhood included QTc duration >500 msec (HR=2.72 [95%CI 1.50 - 4.92]; p=0.001) and prior syncope (recent syncope [<2 years]: HR=6.16 [95%CI 3.41 - 11.15], p<0.001; remote syncope [≥2 years]: HR=2.67 [95% CI 1.22 - 5.85], p=0.01) in males, whereas prior syncope was the only significant risk factor among females (recent syncope: HR=27.82 [95%CI 9.72 - 79.60], p<0.001]; remote syncope: HR=12.04 [95%CI 3.79 - 38.26], p<0.001). β-blocker therapy was associated with a significant 53% reduction in the risk of ACA or SCD (p=0.01).

Conclusions

LQTS males experience a significantly higher rate of fatal or near-fatal cardiac events than females during childhood. A QTc duration >500 msec and a history of prior syncope identify risk in males, whereas prior syncope is the only significant risk factor among females. β-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood.

The congenital long-QT syndrome (LQTS) is caused by mutations that encode channels that regulate sodium, potassium, and calcium currents, and by a mutation in a cytoskeletal gene (ankyrin B) that affects sodium and calcium kinetics, resulting in prolonged ventricular repolarization and an increased risk for sustained ventricular tachyarrhythmias.¹ The genetic disorder is an important cause of sudden cardiac death (SCD) in children without structural heart disease.² However, the risk in affected patients is not uniform due to variable penetrance and is influenced by age, gender, genotype, environmental factors, therapy, and possibly other modifier genes.³ In recent years, numerous advances have been made in the identification of genotype-phenotype relationship and risk factors for cardiac events in LQTS patients.^4-11 These data, however, were assessed mostly in studies that have included syncope as the predominant component in a composite cardiac event end point.

We have recently described the clinical course of LQTS patients during the adolescent¹² and post-adolescent¹³ periods, and have shown that risk factors in this genetic disorder are age-dependent. However, to date, specific risk factors for life-threatening cardiac events in LQTS children have not been assessed.

The objectives of the present study were: (1) to evaluate the contribution of prespecified genetic and clinical factors to the development of aborted cardiac arrest (ACA) or SCD in LQTS children; (2) to determine whether interactions among risk factors can be used to identify risk subsets in this population; and (3) to assess the efficacy of β-blocker therapy for the prevention of fatal or near-fatal cardiac events during childhood within the identified risk-groups.

Methods

Study population

The study population was drawn from the International LQTS Registry and involved children from proband-identified families.⁴ Children older than 1 year of age were considered to have LQTS if (1) the QT interval corrected for heart rate ([QTc] assessed using Bazett's formulae¹⁴) was ≥ 450 msec or (2) they had a documented LQTS mutation by genetic testing. Children were excluded from the analysis if they (1) had a QTc < 450 msec on the baseline ECG without a genotype positive mutation; (2) experienced ACA or death, or were lost to follow-up, before the age of 1 year; (3) were >2^nd degree relatives of probands due to lack of complete information in the registry regarding the clinical course of more distant relatives of probands.

The final study group comprised 3015 children from 1249 proband-identified families, of whom 875 subjects from 272 enrolled families underwent genetic testing and were identified as carriers of a known LQTS mutation. The LQTS genotype was determined using standard mutational analytic techniques involving 5 established genetic laboratories associated with the International LQTS Registry.

Data collection and management

Follow-up was closed on March 30, 2006. Those who did not reach their thirteenth birthday on the date follow-up was closed were censored at the time of their last contact. Those who were lost to follow-up were also censored at the time of their last contact. Among the 3015 study patients, the mean (±SD) age at enrollment in the registry was 7.5 ± 5.4 years. Upon enrollment, complete past history was obtained from birth to their enrolled age, and ongoing clinical information was obtained at yearly intervals thereafter. In the present study we assessed the clinical course of study patients from age 1 through 12 years. Thus, follow-up time for each study patient comprised historical clinical information from age 1 year to enrollment and prospective follow-up information from enrollment through age 12 years, if the patient had not otherwise been censored for any of the above reasons. For each patient, data on personal and family history, cardiac events, and therapy were systematically recorded at enrollment and at each visit or medical contact. Clinical data were recorded on prospectively designed forms and included patient and family history and demographic, ECG, therapeutic, and cardiac event information.

Data regarding β-blocker therapy included the starting date, type of β-blocker, and discontinuation date in case it occurred. After a fatal event, the usage of a β-blocker before death was determined retrospectively.

Among the 3015 study patient, 2 patients died from non-LQTS causes, 32 were lost to follow-up and censored at the time of their last contact, and 329 had not reached their 13^th birthday when follow-up was closed.

All patients or their guardians provided informed consent agreeing to inclusion in the registry and subsequent clinical studies. The study was approved by the University of Rochester Medical Center Institutional Review Board.

End point

The primary end point of the study was time to ACA (requiring external defibrillation as part of the resuscitation) or LQTS-related SCD (death abrupt in onset without evident cause, if witnessed, or death that was not explained by any other cause if it occurred in a nonwitnessed setting such as sleep), whichever occurred first, from age 1 through 12 years.

Statistical analysis

The clinical characteristics of study patients were compared by gender using the chi-square test for categorical variables, and the t-test (and the Mann-Whitney-Wilcoxon test used for comparison between drug dosages) for continuous variables. The Kaplan-Meier estimator was used to assess the time to a first life-threatening event and the cumulative event rates by risk factors and risk groups, and groups were compared using the log-rank test.

Multivariable Cox proportional hazards regression analysis was carried out in the total study population, and separately in the subset of study patients who were genetically tested and identified as carriers of a known LQTS mutation. Prespecified candidate risk factors in the total population model included male gender, syncope (defined as transient loss of consciousness that was abrupt in onset and offset), family history of SCD in a first degree relative, QTc duration > 500 msec on the baseline ECG, and congenital deafness. The occurrence of SCD in a family member and the occurrence of syncope in an affected individual were evaluated in a time-dependent manner. In order to evaluate the independent contribution of the timing of non-life-threatening cardiac events to the development of ACA or SCD, syncopal history was modeled as a 3-level time-dependent categorical predictor X(t): X_i(t) = “recent” if subject i had 1+ events during the time interval [t − 2 years, t); X_i(t) = “remote” if 1+ events during [-1 year, t − 2 years), but no events during [t − 2 years, t); X_i(t) = “none” if no events between birth (t = -1 year, due to the time origin of age 1 year) and time t. Interactions between predictors found to be significantly associated with the outcome were further evaluated in the multivariable Cox models. Interactions between risk factors were considered if thought to be clinically plausible, and included in the model if the ratio of the hazard ratios for the risk factors across patient subsets was >2.5 with p<0.1. Since therapy with β-blockers was given at the discretion of each subject's attending physician to those considered to be at a high-risk, the efficacy of time-dependent β-blocker therapy in reducing the risk of the end point was also related to the presence of risk factors via prespecified β-blocker × risk factor interaction terms.

In the model that included only genetically tested individuals, findings were also adjusted for the presence of the 3 main LQTS genotypes (LQT1, LQT3 and LQT3), and other genotypes (LQT5-8 [n=11] that were included as a single covariate). Patients who had multiple mutations in different genes (n=14) were not included in the genotyped model. Since patients who underwent genetic testing did not have a QTc threshold for exclusion from the study, we carried out an additional exploratory analysis in this population, in which QTc was further categorized into <450 msec, 450-500 msec and >500 msec subgroups, to assess the rate of life-threatening cardiac events in LQTS children with low-normal QTc durations.

All models were stratified by the decade in which study patients were born to account for changes in the baseline hazard function for different calendar time- periods. No adjustments for potential dependencies due to family membership were required since no more than one ACA/SCD was observed from age 1-12 in any given family.¹⁵

The statistical software used for the analyses was SAS version 9.13 (SAS Institute Inc, Cary, NC). A 2-sided 0.05 significance level was used for hypothesis testing, while the 2-tailed 0.10 level was used for including predictors in the Cox models.

The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

Results

Study population

The clinical characteristics of study patients by gender are shown in Table 1A. Females comprised 63% of patients and had a significantly longer QTc duration as compared with males, whereas other ECG parameters were similar in males and females.

Table 1.

Characteristics of study patients by gender.

A. Clinical, electrocardiographic, and genetic characteristics.*

	Female (n=1893)	Male (n=1122)	p-value
Family history of SCD, n (%)	83 (4)	65 (6)	0.08
Congenital deafness, n (%)	35 (2)	24 (2)	0.58
Baseline ECG data
QTc, msec
Mean (±SD)	493 ± 49	489 ± 48	0.01
Median (IQ-range)	480 (460, 510)	480 (460, 510)
QTc > 500 msec, n (%)	654 (35)	387 (34)	0.98
RR, msec	834 ± 202	834 ± 223	NA†
QRS, msec	81 ± 2	83 ± 2┼	NA†
PR, msec	150 ± 27	150 ± 30	>0.99
Genotype
Total, n (%) N=875	510 (27)	365 (33)	0.005
LQT1, n (% of genotyped pts.)	270 (53)	188 (51)	0.48
LQT2, n (% of genotype pts.)	191 (37)	136 (37)	0.41
LQT3, n (% of genotyped pts.)	33 (6)	32 (9)	0.17
Other, n. (% of genotyped pts.)‡	8 (2)	3 (1)	0.38
Multiple mutations in different genes, n (% of genotyped pts)	8 (2)	6 (2)	0.93
*Plus – minus values are means ± SD..
†Since heart and QRS duration are age-dependent and ECGs were recorded at different ages, no statistical comparisons were made between males and females for these 2 ECG parameters.
‡Denotes patients who were identified as carriers of LQT5-8.
ECG = electrocardiogram; LQT1, 2, and 3 = long QT syndrome genotypes types 1, 2, and 3, respectively.

B. Clinical course from age 1 through 12 years*
	Female (n=1893)	Male (n=1122)	p-value
Mean follow-up time. yrs┼	11.6 ± 1.7	11.2 ± 2.2	<0.001
Medications‡
β-blockers
Overall, n (%)§	285 (15)	358 (32)	<0.001
Subtypes:
Propranolol, n (% of β-blockers used)	192 (67)	205 (57)	0.01
Last recorded dose before age 13, mg	75 ± 51	85 ± 61	0.31
Atenolol, n (% of β-blockers used)	97 (34)	145 (40)	0.10
Last recorded dose before age 13, mg	51 ± 35	51 ± 34	0.97
Nadolol, n (% of β-blockers used)	66 (23)	96 (27)	0.30
Last recorded dose before age 13, mg	57 ± 49	50 ± 35	0.70
Metoprolol, n (% of β-blockers used)	9 (3)	18 (5)	0.24
Last recorded dose before age 13, mg	119 ± 72	89 ± 55	0.41
Other, n (% of β-blockers used)¶	10 (3)	9 (3)	0.46
Flecainide, no (%)	3 (0.2)	2 (0.2)	1.00
Last recorded dose before age 13, mg	167 ± 58	163 ± 124	0.96
Mexiletine, n (%)	12 (1)	17 (2)	0.02
Last recorded dose before age 13, mg	373 ± 180	280 ± 167	0.18
Other LQTS-related therapies
LCSD, n (%)	16 (1)	23 (2)	0.005
Pacemaker, no (%)	19 (1)	33 (3)	<0.001
ICD n (%)	15 (1)	26 (2)	<0.001
Cardiac events
Syncope, n (%)	331 (17)	262 (23)	<0.001
ACA, n (%)	17 (1)	36 (3)	<0.001
SCD, n (%)	4 (0.2)	21 (2)	<0.001
First occurrence of ACA or SCD, n (%)	20 (1)	53 (5)	<0.001

^*Plus – minus values are means ± SD..

^┼Comprises complete clinical history prior to enrollment and yearly follow-up data after enrollment.

^‡Denotes patients who were treated with the medications at any time during follow-up.

^§180 patients (28%) were treated during childhood with different types of β-blockers.

^¶Other β-blockers included bisoprolol, labetolol, betaxolol, acebutolol, and pindolol.

ACA = aborted cardiac arrest; ICD = implantable cardioverter defibrillator; LCSD = left cervical sympathetic denervation; SCD = sudden cardiac death.

Male patients exhibited a significantly higher proportion of all types of LQTS-related cardiac events during follow-up as compared with females, and accordingly received a higher proportion of medical and non-medical therapies for the genetic disorder (Table 1B).

Genotyped patients had a gender distribution (Table 1A) and a mean QTc duration (490 ± 54 msec) that were similar to the total population. However, patients who underwent genetic testing displayed several important clinical differences from non-genotyped individuals including, a lower frequency of probands (31% vs. 45%, respectively; p<0.001), a higher frequency of SCD in affected family members (9% vs. 4%, respectively; p<0.001), and a higher frequency of therapy with β-blockers during follow-up (22% vs. 18%, respectively; p=0.006). Accordingly, the subset of study patients who were genotyped experienced a relatively low rate of LQTS-related life-threatening cardiac events during childhood (ACA: 1.2%; SCD: 0.5%).

Risk factors for life-threatening cardiac events in LQTS children

Total population

male gender, time dependent syncope, and a QTc duration > 500 msec were identified as significant predictors of life-threatening cardiac events during childhood among study patients. Furthermore, the effect of each of these 3 clinical factors displayed important differences among risk-subsets of LQTS children (Tables 2A and B, with the corresponding number of patients, follow-up time, and crude event rates for each risk subset provided in the Supplementary Appendix). By contrast, a family history of SCD in a first degree relative was not shown to be a significant predictor of outcome during childhood (hazard ratio [HR] = 0.82 (95% confidence interval [CI] 0.26 - 2.60; p=0.73). Patients born with congenital deafness had more than a 3-fold increase in the risk of life-threatening cardiac events during childhood without adjustment for a history of prior syncope (unadjusted HR = 3.22 [95% CI 1.38 - 7.49]; p=0.007). However, when time-dependent syncope was added to the multivariable model, the risk associated with congenital deafness was no longer evident (adjusted HR = 0.89 [95% CI 0.38 - 2.15]; p=0.80). Of note, virtually identical results regarding risk factors were obtained after patients who were born with congenital deafness were removed from the analysis.

Table 2. Risk factors for aborted cardiac arrest or sudden cardiac death during childhood.

A. Male vs. female hazard ratio in risk subsets.*^†

Risk Subset	Males vs. Female Risk
	Hazard Ratio (95% CI)	p-value
No prior syncope and:
QTc >500 msec	12.11 (3.73 - 39.31)	<0.001
QTc ≤500 msec	4.23 (1.47 - 12.19)	0.008
Prior syncope and:
QTc >500 msec	2.68 (1.22 - 5.91)	0.01
QTc ≤500 msec	0.94 (0.38 - 2.30)	0.88
*Findings are derived from the main interaction model that was identified to have the best fit for the data. Covariates and interactions in the model included: recent syncope (<2 years) vs. no syncope, remote syncope (≥2 years) vs. no syncope; QTc duration; gender; gender × prior syncope (at anytime during childhood) interaction, and gender × QTc interaction.
†See Supplementary Appendix for corresponding patient counts, follow-up time, events, and crude event rate in each risk subset.

B. Risk factors for males and females.*†
Risk factor	Males		Females		Interaction p-value‡
	HR (95% CI)	p-value	HR (95% CI)	p-value
QTc duration
QTc >500 msec vs. QTc ≤500 msec	2.72 (1.50 - 4.92)	0.001	0.95 (0.39 - 2.33)	0.91	0.055
Prior syncope
Recent (<2 years) vs. No syncope	6.16 (3.41 - 11.15)	<0.001	27.82 (9.72 - 79.60)	<0.001	0.01‡
Remote (≥2 years) vs. No syncope	2.67 (1.22 - 5.85)	0.01	12.04 (3.79 - 38.26)	<0.001

^*Findings are derived from the main interaction model that was identified to have the best fit for the data. Covariates and interactions in the model included: recent syncope (<2 years) vs. no syncope, remote syncope (≥2 years) vs. no syncope; QTc duration; gender; gender × prior syncope (at anytime during childhood) interaction, and gender × QTc interaction.

^†See Supplementary Appendix for corresponding patient counts, follow-up time, events, and crude event rate in each risk subset.

^‡Denotes the p-value for interaction between gender and each risk factor.

The interaction terms for recent syncope × gender and remote syncope × gender were similar. Therefore, the interaction for any prior syncope × gender was included in the multivariable model.

Male patients experienced a significantly higher rate of life-threatening cardiac events during childhood (5%) than females (1%; Fig. 1). The relative risk of males versus females was most pronounced in asymptomatic (e.g. without prior syncope) LQTS children who had a prolonged QTc duration, and attenuated after an LQTS child became symptomatic (e.g. experienced syncope) during follow-up (Table 2A).

Figure 1.

Kaplan-Meier estimates of the probability of ACA or SCD by gender (values in parentheses are event rates).

A QTc duration > 500 msec was associated with nearly a 3-fold increase in the risk of fatal or near-fatal events in LQTS males, whereas QTc duration was not a significant risk factor among females (Table 2B). Accordingly, the cumulative rate of ACA or SCD during childhood was significantly higher among boys with a QTc duration > 500 msec than among boys with a shorter QTc duration, or girls regardless of their QTc duration (Fig. 2).

Figure 2.

Kaplan-Meier estimates of the probability of ACA or SCD by gender and QTc subgroups (values in parentheses are event rates).

Time-dependent syncope was shown to be the most powerful predictor of outcome in both LQTS males and females (Table 2B). Notably, the risk associated with a history of syncope was significantly higher in females than in males (p-value for gender × prior syncope interaction = 0.01), and most pronounced when the event occurred within the past 2-years. However, even more remote syncope was associated with a significant and substantial increase in the risk of subsequent life-threatening events during childhood in both males and females (Table 2B).

The nature of time-dependent covariates precludes assessment of cumulative event rates based only on the covariate pattern at the time origin. Therefore, to obtain an estimate of event rates during childhood for patients who experienced syncope during follow-up, we identified time-independent risk groups at age 6 years, stratified by the occurrence of syncope prior to age 6, and evaluated the cumulative probability of ACA or SCD from age 6 through 12 years (Fig. 3). This analysis demonstrated that the rate of life-threatening events during childhood was highest among boys who experienced prior syncope (15%), intermediate in girls with a history of syncope and asymptomatic boys (4% and 3%, respectively), and lowest in girls without a history of prior syncope (0.6%; p<0.001).

Figure 3.

Kaplan-Meier estimates of the probability of ACA or SCD after age 6 years by gender and a history of syncope before the 6^th birthday (values in parentheses are event rates). W/Syncope = with syncope.

Genotyped patients

When predictors of life-threatening cardiac events were analyzed in the subgroup of LQTS children who were genotyped, clinical factors, including time-dependent syncope (HR = 4.23 [95% CI 1.13 - 15.85]; p=0.03) and male gender (HR=5.05 [95% CI 1.08 - 23.53]; p=0.04) were identified as predictors of outcome, whereas non-significant differences in the risk for life-threatening cardiac events were shown among the three major LQTS genotypes (LQT1 vs. LQT2: HR = 1.83 [95% CI 0.36 - 9.17], p=0.46; LQT3 vs. LQT2: HR = 2.95 [95% CI 0.26- -33.16], p=0.38; LQT3 vs. LQT1: HR = 1.62 [95% CI 0.18 – 14.47], p=0.67). Interactions among clinical factors, and between clinical factors and genotypes, were not significant in the model that included the genotyped population, possibly due to the relatively low event rate in this subset of study patients.

A QTc duration >500 msec was associated with a statistically non-significant >2-fold increase in the risk of ACA or SCD in the genotyped population (HR = 2.68 [95% CI 0.69 – 10.49] = 0.16). Notably, no life-threatening cardiac events occurred in genotyped patients who exhibited low to normal QTc durations (<450 msec [n=127]), whereas the cumulative probability of ACA or death in patients with intermediate- (450-500 msec [n=437]) and high- (>500 msec [n=239]) QTc durations was 1% and 3%, respectively (p=0.037 for the comparison among the 3 QTc subgroups).

β-blocker efficacy during childhood

β-blocker therapy was initiated at some point during childhood for 643 (21%) study patients, of whom 67 (10%) discontinued the medication before termination of follow-up The main β-blocker subtypes and their respective mean dosages are shown in Table 1B.

Patients who were treated with β-blockers during childhood had a higher frequency of risk factors as compared with untreated LQTS children (QTc duration: 501±50 msec vs. 489±48, respectively [p<0.001]; prior syncope: 52% vs. 12%, respectively [p<0.001]; male gender: 56% vs. 33%, respectively [p<0.001]).

In multivariable analysis, β-blocker therapy was independently associated with a significant 53% reduction in the risk of ACA or SCD during childhood (HR=0.47 [95% CI 0.26 – 0.85]; p=0.01). The benefit of β-blocker therapy was pronounced among high-risk children who experienced syncope during the past 2 years (HR=0.27 [95% CI 0.12 - 0.62]; p=0.002), and significantly attenuated (HR=0.95 [95% CI 0.41 – 2.21]; p=0.90) in lower-risk children with more remote or no syncope (p-value for β-blocker × recent syncope interaction = 0.03). However, despite the significant beneficial effects of β-blockers, the rate of life-threatening cardiac events among high-risk children who were treated with β-blockers was considerable: boys on β-blockers as of age 6 who experienced syncope prior to age 6 had a 12% cumulative probability of ACA or SCD during the subsequent 7 years of follow-up, corresponding to an average annual event rate of nearly 2% while on medical therapy.

Other LQTS-related therapies during childhood

Additional therapeutic modalities were employed infrequently during childhood, and are considered separately below.

Medical therapy with mexiletine and flecainide were administered to a small number of study patients (Table 1B). Twenty-nine study patients received mexiletine, of whom 2 (7%) had ACA or SCD during treatment. Flecainide was administered to only 5 patients (comprising mostly LQT3 genotype carriers or their family members), of whom 1 experienced SCD during therapy.

Forty one study patients (1%) received an implantable cardioverter defibrillator (ICD) during childhood. The device was implanted at a mean (±SD) age of 7.3 ± 0.5 years. Twelve patients experienced ACA prior to implantation, and 29 experienced at least one episode of syncope prior to implantation (mean [±SD] 2.5 ± 0.4 episodes). The combined endpoint of ACA or SCD occurred in 1 patient who was affected with Timothy syndrome (ICD implanted at age 2.5 years due to recurrent syncope despite β-blocker therapy; age at death: 5.1 years; mode of death: electrical storm [persistent torsade de pointes despite 25 ICD shocks]) during a mean (±SD) follow-up period of 2.7 ± 0.3 years. Interrogation data were available for a subset of 20 (49%) LQTS children with an ICD, of whom 8 (40%) experienced at least one appropriate ICD discharge during the same follow-up period.

Left cervical sympathetic denervation was carried out in 40 patients (1%) during childhood. The procedure was performed at a mean (±SD) age of 7.4 ± 0.4 years. Similar to patients treated with an ICD, children who underwent LCSD experienced prior syncope (n=27) or prior ACA (n=13). None of the patients who underwent LCSD experienced a life-threatening cardiac event after the procedure during a mean (±SD) follow-up period of 3.9 ± 0.4 years

A cardiac pacemaker was implanted in 70 children at a mean (±SD) age of 6.2 ± 0.4 years, 9 of whom had ACA prior to implantation. The combined endpoint of ACA or SCD occurred in 6 patients after implantation of a pacemaker during a mean (±SD) follow-up period of 4.0 ± 0.5 years.

Discussion

Three main implications emerge from the present study regarding the risk of life-threatening cardiac events in LQTS children: (1) risk factors for ACA or SCD can be assessed from clinical history and examination of the ECG, and include male gender, a history of syncope at any time during childhood, and a QTc duration > 500 msec; (2) significant interactions exist among the 3 clinical risk factors that can identify risk subsets in this population; and (3) β-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events in LQTS children. However, the rate of ACA or SCD in high-risk children who experience syncope is still considerable despite β-blocker therapy.

The current study is the first to focus solely on the end point of life-threatening cardiac events in young, pre-adolescent LQTS children. We have shown that the rate of fatal or near-fatal events in children with this genetic disorder is significantly higher among boys than among girls throughout childhood, resulting in a significantly higher cumulative event rate in pre-adolescent boys, despite the fact that females exhibited a significantly longer mean QTc duration, and had similar baseline heart rates. Notably, asymptomatic males with a prolonged QTc duration exhibited more than a 12-fold increase in the risk of life-threatening cardiac events as compared with the respective females, whereas after the occurrence of syncope during follow-up the relative risk associated with male gender was attenuated.

Our findings are consistent with previous data regarding gender differences in the risk of LQTS-related cardiac events.^8,9 Two recent studies from the International LQTS Registry that have focused on LQTS adolescents¹² and adults¹³ demonstrated that the gender-related risk reverses after childhood, and females maintain higher risk than males throughout adolescence and during adulthood. The mechanisms behind these age-dependent differences in gender-related risk are unknown. The predominance of life-threatening cardiac events among males during the first decade of life may be related to environmental factors or to the presence of modifier genes, whereas the opposing effects of estrogen and androgens on ventricular repolarization (increase and decrease in QTc duration, respectively) have been suggested as a possible mechanism for the male vs. female risk-reversal with the onset of adolescence.^16-19 Ventricular tachyarrhythmias have been shown to occur more frequently during physical effort in patients carrying the common LQT1 genotype,¹¹ possibly due to lack of adaptive QT shortening with decreasing RR intervals during tachycardia.²⁰ Boys may participate more frequently in intensive physical activity than girls during childhood due to environmental influences, and this factor may contribute to the gender-related risk of life-threatening tachyarrhythmias in this age-group. It is also possible that there are modifier genes that are not shared by males and females (e.g. on the Y chromosome) that contribute to the higher risk of LQTS males early in life. Thus, interactions among environmental, genetic and hormonal factors need to be further evaluated in this genetic disorder. At present, our data suggest that LQTS boys should be followed-up carefully for both QTc duration and the development of clinical symptoms, and be offered primary therapies for this genetic disorder during childhood based upon either of these two risk factors; whereas LQTS girls who do not experience syncope appear to maintain a relatively low risk for ACA or SCD during childhood regardless of their QTc duration.

Genotype data have been shown to be useful for risk-stratification in LQTS patients when syncope is a component of the cardiac endpoint.^6,7 However, in the current study, a history of syncope was employed as a time-dependent covariate in the multivariable model that assessed the endpoint of ACA or SCD. Using this methodology we have shown that among genotyped study patients, data regarding a specific genotype (LQT1, 2, or 3) did not contribute significantly to outcome, whereas clinical risk factors, including male gender and time-dependent syncope, maintained their significance as powerful predictors of outcome. Nevertheless, only 2% of genotyped patients experienced a fatal or near-fatal event during childhood. Thus, it is possible that the study may be underpowered to detect statistically significant differences in the risk conferred by the 3 main LQTS genotypes or interactions between clinical factors and genotypes. Similarly, despite the fact that children born with congenital deafness experienced a significantly higher frequency of life-threatening cardiac events (10%) as compared with those without congenital deafness (2%), this factor did not make a significant contribution to outcome after multivariable adjustment, possibly due to the fact that all patients with congenital deafness who had a life-threatening cardiac event during childhood also experienced syncope prior to the event, making the latter symptom the predominant risk factor in the multivariable model.

β-blocker therapy was associated with a significant reduction in the risk of life-threatening cardiac events in the study population, with a more pronounced effect in high-risk patients who experienced recent syncope, suggesting that this mode of medical therapy should be considered a first line measure in LQTS children. The lack of a significant effect of β-blocker therapy in lower-risk patients does not imply that this mode of medical therapy should not be prescribed to symptomatic males or females with remote syncope or males with a prolonged QTc interval duration. Prescription of β-blockers was administered to those considered to be at risk by the treating physician, and unmeasured risk factors may have been more unbalanced in patients with lower-risk features. Nevertheless, despite the highly significant beneficial effects of β-blockers in high-risk children and possible beneficial effects in lower-risk subsets, children with a history of syncope who were treated with β-blockers still displayed a substantial burden of life-threatening events while on medical therapy. Other therapeutic modalities including implantation of an ICD and LCSD have been shown to be effective in LQTS patients.^21,22 These more invasive medical procedures should be considered for the primary prevention of life-threatening cardiac events in LQTS children in whom symptoms persist despite β-blocker therapy.

Limitations

Despite the relatively large sample size of the current study, there were only 53 first life-threatening cardiac events in males and, more importantly, only 20 among females. This relatively low event rate, especially among females, could have contributed to the unexpectedly large 12- to 28-fold hazard-ratio estimates for remote and recent syncope among girls, as well as the 4.5-fold interaction of gender with syncope. Therefore, although these effects were statistically significant at the 0.01 level, future analyses of the expanding LQTS Registry may be needed to validate and better estimate the identified interactions with gender, the relative risks among females, and the effect of genetic factors on outcome during childhood.

Conclusions and clinical implications

The current study of LQTS children and a recent report from the International LQTS Registry on the clinical course of LQTS adolescents¹² consistently demonstrate that risk factors for life-threatening cardiac events can be assessed from clinical history and the surface ECG. Importantly, the results of the two studies suggest that careful follow-up is warranted in LQTS patients since risk factors for life-threatening cardiac events are time-dependent and age-specific, resulting in a substantial variability in the phenotypic expression of this genetic disorder during long-term follow-up.