Beta-Blocker Efficacy in Patients With Congenital Long-QT Syndrome
Beta-Blocker Efficacy in Patients With Congenital Long-QT Syndrome
β-Blockers for LQTS Types 1 and 2.
Background: Beta-blockers are the mainstay therapy in patients with the congenital long-QT syndrome (LQTS) types 1 and 2. However, limited data exist regarding the efficacy and limitations of this form of medical management within high-risk subsets of these populations.
Methods and Results: Multivariate analysis was carried out to identify age-related gender- and genotype-specific risk factors for cardiac events (comprising syncope, aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years among 971 LQT1 (n = 549) and LQT2 (n = 422) patients from the International LQTS Registry. Risk factors for cardiac events included the LQT1 genotype (HR = 1.49, P = 0.003) and male gender (HR = 1.31, P = 0.04) in the 0–14 years age group; and the LQT2 genotype (HR = 1.67, P < 0.001) and female gender (HR = 2.58, P < 0.001) in the 15–40 years age group. Gender–genotype subset analysis showed enhanced risk among LQT1 males (HR = 1.93, P < 0.001) and LQT2 females (HR = 3.28, P < 0.001) in the 2 respective age groups. Beta-blocker therapy was associated with a significant risk-reduction in high-risk patients, including a 67% reduction (P = 0.02) in LQT1 males and a 71% reduction (P < 0.001) in LQT2 females. Life-threatening events (ACA/SCD) rarely occurred as a presenting symptom among beta-blocker-treated patients. However, high-risk patients who experienced syncope during beta-blocker therapy had a relatively high rate of subsequent ACA/SCD (>1 event per 100 patient-years).
Conclusions: The present findings suggest that beta-blocker therapy should be routinely administered to all high-risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy.
The congenital long-QT syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity for polymorphic ventricular tachyarrhythmias and sudden cardiac death (SCD) in young individuals with normal cardiac morphology. To date, more than 500 mutations have been identified in 12 LQTS genotypes, with the LQTS type 1 (LQT1) and LQTS type 2 (LQT2) genotypes accounting for nearly 90% of identified cases.
LQT1 patients, who harbor mutations impairing IKs, have been shown to experience the majority of their events during exercise. This may be due to the fact that the repolarizing current IKs activates during increased heart rate, and is essential for QT interval adaptation during tachycardia. Similarly, most cardiac events in LQT2 patients, harboring mutations impairing IKr, are triggered by increased sympathetic activity associated with arousal episodes. Accordingly, beta-blockers are the mainstay medical therapy in these LQTS populations. By contrast, the efficacy of beta-blocker therapy appears to be more limited among LQTS type 3 patients who exhibit excessive further prolongation of the QT interval at slow heart rates. Despite the sympathetic mechanisms associated with the 2 main LQTS genotypes, previous studies that assessed efficacy of beta-blocker therapy in LQT1 and LQT2 patients have suggested important limitations of this mode of medical therapy among treated patients. These studies, however, were limited by a relatively small sample size of genotyped patients. Furthermore, there are no data regarding the efficacy and limitations of medical therapy in age–gender risk-subsets of genotyped patients, despite the fact that the clinical course of male and female LQT1 and LQT2 patients exhibits significant age-related differences. This study was undertaken to: (1) identify high-risk subsets of LQT1 and LQT2 patients, categorized by gender and genotype; (2) evaluate the efficacy of beta-blocker therapy within the identified risk-subsets; (3) assess the residual event rate during beta-blocker therapy among high-risk LQTS patients; and (4) propose a possible strategy for the management of LQT1 and LQT2 patients based on our findings.
Abstract and Introduction
Abstract
β-Blockers for LQTS Types 1 and 2.
Background: Beta-blockers are the mainstay therapy in patients with the congenital long-QT syndrome (LQTS) types 1 and 2. However, limited data exist regarding the efficacy and limitations of this form of medical management within high-risk subsets of these populations.
Methods and Results: Multivariate analysis was carried out to identify age-related gender- and genotype-specific risk factors for cardiac events (comprising syncope, aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years among 971 LQT1 (n = 549) and LQT2 (n = 422) patients from the International LQTS Registry. Risk factors for cardiac events included the LQT1 genotype (HR = 1.49, P = 0.003) and male gender (HR = 1.31, P = 0.04) in the 0–14 years age group; and the LQT2 genotype (HR = 1.67, P < 0.001) and female gender (HR = 2.58, P < 0.001) in the 15–40 years age group. Gender–genotype subset analysis showed enhanced risk among LQT1 males (HR = 1.93, P < 0.001) and LQT2 females (HR = 3.28, P < 0.001) in the 2 respective age groups. Beta-blocker therapy was associated with a significant risk-reduction in high-risk patients, including a 67% reduction (P = 0.02) in LQT1 males and a 71% reduction (P < 0.001) in LQT2 females. Life-threatening events (ACA/SCD) rarely occurred as a presenting symptom among beta-blocker-treated patients. However, high-risk patients who experienced syncope during beta-blocker therapy had a relatively high rate of subsequent ACA/SCD (>1 event per 100 patient-years).
Conclusions: The present findings suggest that beta-blocker therapy should be routinely administered to all high-risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy.
Introduction
The congenital long-QT syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity for polymorphic ventricular tachyarrhythmias and sudden cardiac death (SCD) in young individuals with normal cardiac morphology. To date, more than 500 mutations have been identified in 12 LQTS genotypes, with the LQTS type 1 (LQT1) and LQTS type 2 (LQT2) genotypes accounting for nearly 90% of identified cases.
LQT1 patients, who harbor mutations impairing IKs, have been shown to experience the majority of their events during exercise. This may be due to the fact that the repolarizing current IKs activates during increased heart rate, and is essential for QT interval adaptation during tachycardia. Similarly, most cardiac events in LQT2 patients, harboring mutations impairing IKr, are triggered by increased sympathetic activity associated with arousal episodes. Accordingly, beta-blockers are the mainstay medical therapy in these LQTS populations. By contrast, the efficacy of beta-blocker therapy appears to be more limited among LQTS type 3 patients who exhibit excessive further prolongation of the QT interval at slow heart rates. Despite the sympathetic mechanisms associated with the 2 main LQTS genotypes, previous studies that assessed efficacy of beta-blocker therapy in LQT1 and LQT2 patients have suggested important limitations of this mode of medical therapy among treated patients. These studies, however, were limited by a relatively small sample size of genotyped patients. Furthermore, there are no data regarding the efficacy and limitations of medical therapy in age–gender risk-subsets of genotyped patients, despite the fact that the clinical course of male and female LQT1 and LQT2 patients exhibits significant age-related differences. This study was undertaken to: (1) identify high-risk subsets of LQT1 and LQT2 patients, categorized by gender and genotype; (2) evaluate the efficacy of beta-blocker therapy within the identified risk-subsets; (3) assess the residual event rate during beta-blocker therapy among high-risk LQTS patients; and (4) propose a possible strategy for the management of LQT1 and LQT2 patients based on our findings.
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