Risk of death in the long QT syndrome when a sibling has died

BACKGROUND: Sudden death of a sibling is thought to be associated with greater risk of death in long QT syndrome (LQTS). However, there is no evidence of such an association. OBJECTIVE: This study sought to test the hypothesis that sudden death of a sibling is a risk factor for death or aborted cardiac arrest (ACA) in patients with LQTS. METHODS: We examined all probands and first-degree and second-degree relatives in the International Long QT Registry from birth to age 40 years with QTc >/= 0.45 s. Covariates included sibling death, QTc, gender by age, syncope, and implantable cardioverter-defibrillator (ICD) and beta-blocker treatment. End points were (1) severe events (ACA, LQTS-related death) and (2) any cardiac event (syncope, ACA, or LQTS-related death). RESULTS: Of 1915 subjects, 270 had a sibling who died. There were 213 severe events and 829 total cardiac events. More subjects with history of sibling death received beta-blocker therapy. Sibling death was not significantly associated with risk of ACA or LQTS-related death, but was associated with increased risk of syncope. QTc >/= 0.53 s (hazard ratio 2.5, P <.01), history of syncope (hazard ratio 6.1, P <.01), and gender were strongly associated with risk of ACA or LQTS-related death. CONCLUSION: Sudden death of a sibling prompted more aggressive treatment but did not predict risk of death or ACA, whereas QTc >/= 0.53 s, gender, and syncope predicted this risk. All subjects should receive appropriate beta-blocker therapy. The decision to implant an ICD should be based on an individual's own risk characteristics (QTc, gender, and history of syncope)

Effectiveness and limitations of β-blocker therapy in congenital long-QT syndrome

Background—β-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of β-blockers in this disorder have not been evaluated. Methods and Results—The study population comprised 869 LQTS patients treated with β-blockers. Effectiveness of β-blockers was analyzed during matched periods before and after starting β-blocker therapy, and by survivorship methods to determine factors associated with cardiac events while on prescribed β-blockers. After initiation of β-blockers, there was a significant (P<0.001) reduction in the rate of cardiac events in probands (0.97±1.42 to 0.31±0.86 events per year) and in affected family members (0.26±0.84 to 0.15±0.69 events per year) during 5-year matched periods. On-therapy survivorship analyses revealed that patients with cardiac symptoms before β-blockers (n=598) had a hazard ratio of 5.8 (95% CI, 3.7 to 9.1) for recurrent cardiac events (syncope, aborted cardiac arrest, or death) during β-blocker therapy compared with ..

Long QT Syndrome and Pregnancy

ObjectivesThis study was designed to investigate the clinical course of women with long QT syndrome (LQTS) throughout their potential childbearing years.BackgroundOnly limited data exist regarding the risks associated with pregnancy in women with LQTS.MethodsThe risk of experiencing an adverse cardiac event, including syncope, aborted cardiac arrest, and sudden death, during and after pregnancy was analyzed for women who had their first birth from 1980 to 2003 (n = 391). Time-dependent Kaplan-Meier and Cox proportional hazard methods were used to evaluate the risk of cardiac events during different peripartum periods.ResultsCompared with a time period before a woman’s first conception, the pregnancy time was associated with a reduced risk of cardiac events (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.10 to 0.76, p = 0.01), whereas the 9-month postpartum time had an increased risk (HR 2.7, 95% CI 1.8 to 4.3, p < 0.001). After the 9-month postpartum period, the risk was similar to the period before the first conception (HR 0.91, 95% CI 0.55 to 1.5, p = 0.70). Genotype analysis (n = 153) showed that women with the LQT2 genotype were more likely to experience a cardiac event than women with the LQT1 or LQT3 genotype. The cardiac event risk during the high-risk postpartum period was reduced among women using beta-blocker therapy (HR 0.34, 95% CI 0.14 to 0.84, p = 0.02).ConclusionsWomen with LQTS have a reduced risk for cardiac events during pregnancy, but an increased risk during the 9-month postpartum period, especially among women with the LQT2 genotype. Beta-blockers were associated with a reduction in cardiac events during the high-risk postpartum time period

Risk Factors for Recurrent Syncope and Subsequent Fatal or Near-Fatal Events in Children and Adolescents With Long QT Syndrome

ObjectivesWe aimed to identify risk factors for recurrent syncope in children and adolescents with congenital long QT syndrome (LQTS).BackgroundData regarding risk assessment in LQTS after the occurrence of the first syncope episode are limited.MethodsThe Prentice-Williams-Peterson conditional gap time model was used to identify risk factors for recurrent syncope from birth through age 20 years among 1,648 patients from the International Long QT Syndrome Registry.ResultsMultivariate analysis demonstrated that corrected QT interval (QTc) duration (≥500 ms) was a significant predictor of a first syncope episode (hazard ratio: 2.16), whereas QTc effect was attenuated when the end points of the second, third, and fourth syncope episodes were evaluated (hazard ratios: 1.29, 0.99, 0.90, respectively; p < 0.001 for the null hypothesis that all 4 hazard ratios are identical). A genotype-specific subanalysis showed that during childhood (0 to 12 years), males with LQTS type 1 had the highest rate of a first syncope episode (p = 0.001) but exhibited similar rates of subsequent events as other genotype-sex subsets (p = 0.63). In contrast, in the age range of 13 to 20 years, long QT syndrome type 2 females experienced the highest rate of both first and subsequent syncope events (p < 0.001 and p = 0.01, respectively). Patients who experienced ≥1 episodes of syncope had a 6- to 12-fold (p < 0.001 for all) increase in the risk of subsequent fatal/near-fatal events independently of QTc duration. Beta-blocker therapy was associated with a significant reduction in the risk of recurrent syncope and subsequent fatal/near-fatal events.ConclusionsChildren and adolescents who present after an episode of syncope should be considered to be at a high risk of the development of subsequent syncope episodes and fatal/near-fatal events regardless of QTc duration

A Novel and Lethal De Novo LQT-3 Mutation in a Newborn with Distinct Molecular Pharmacology and Therapeutic Response

SCN5A encodes the alpha-subunit (Na(v)1.5) of the principle Na(+) channel in the human heart. Genetic lesions in SCN5A can cause congenital long QT syndrome (LQTS) variant 3 (LQT-3) in adults by disrupting inactivation of the Na(v)1.5 channel. Pharmacological targeting of mutation-altered Na(+) channels has proven promising in developing a gene-specific therapeutic strategy to manage specifically this LQTS variant. SCN5A mutations that cause similar channel dysfunction may also contribute to sudden infant death syndrome (SIDS) and other arrhythmias in newborns, but the prevalence, impact, and therapeutic management of SCN5A mutations may be distinct in infants compared with adults.Here, in a multidisciplinary approach, we report a de novo SCN5A mutation (F1473C) discovered in a newborn presenting with extreme QT prolongation and differential responses to the Na(+) channel blockers flecainide and mexiletine. Our goal was to determine the Na(+) channel phenotype caused by this severe mutation and to determine whether distinct effects of different Na(+) channel blockers on mutant channel activity provide a mechanistic understanding of the distinct therapeutic responsiveness of the mutation carrier. Sequence analysis of the proband revealed the novel missense SCN5A mutation (F1473C) and a common variant in KCNH2 (K897T). Patch clamp analysis of HEK 293 cells transiently transfected with wild-type or mutant Na(+) channels revealed significant changes in channel biophysics, all contributing to the proband's phenotype as predicted by in silico modeling. Furthermore, subtle differences in drug action were detected in correcting mutant channel activity that, together with both the known genetic background and age of the patient, contribute to the distinct therapeutic responses observed clinically.The results of our study provide further evidence of the grave vulnerability of newborns to Na(+) channel defects and suggest that both genetic background and age are particularly important in developing a mutation-specific therapeutic personalized approach to manage disorders in the young

Cardiac sodium channelopathies

Cardiac sodium channel are protein complexes that are expressed in the sarcolemma of cardiomyocytes to carry a large inward depolarizing current (INa) during phase 0 of the cardiac action potential. The importance of INa for normal cardiac electrical activity is reflected by the high incidence of arrhythmias in cardiac sodium channelopathies, i.e., arrhythmogenic diseases in patients with mutations in SCN5A, the gene responsible for the pore-forming ion-conducting α-subunit, or in genes that encode the ancillary β-subunits or regulatory proteins of the cardiac sodium channel. While clinical and genetic studies have laid the foundation for our understanding of cardiac sodium channelopathies by establishing links between arrhythmogenic diseases and mutations in genes that encode various subunits of the cardiac sodium channel, biophysical studies (particularly in heterologous expression systems and transgenic mouse models) have provided insights into the mechanisms by which INa dysfunction causes disease in such channelopathies. It is now recognized that mutations that increase INa delay cardiac repolarization, prolong action potential duration, and cause long QT syndrome, while mutations that reduce INa decrease cardiac excitability, reduce electrical conduction velocity, and induce Brugada syndrome, progressive cardiac conduction disease, sick sinus syndrome, or combinations thereof. Recently, mutation-induced INa dysfunction was also linked to dilated cardiomyopathy, atrial fibrillation, and sudden infant death syndrome. This review describes the structure and function of the cardiac sodium channel and its various subunits, summarizes major cardiac sodium channelopathies and the current knowledge concerning their genetic background and underlying molecular mechanisms, and discusses recent advances in the discovery of mutation-specific therapies in the management of these channelopathies

The Benefits of a Friendship-Based HIV/STI Prevention Intervention for African American Youth

This article presents findings from a qualitative evaluation of an HIV/STI (sexually transmitted infection) prevention intervention for urban African American youth (Project ÒRÉ), which was delivered to groups of 3 to 8 adolescents who were members of the same friendship network. Sixteen focus groups (N = 63) were conducted with youth following their participation in the intervention. Results demonstrate high acceptability of the intervention. Both males and females revealed multiple benefits of attending the intervention with friends including feeling more comfortable, experiencing general satisfaction with the program, experiencing greater ease in talking and expressing self, being able to reveal sensitive information, and being able to relate to each other's experiences. Additional themes were presented only by males including feeling a sense of cohesion, the ability to protect each other from HIV/STIs in the future, and feeling safe. These results suggest that delivering HIV/STI and other prevention interventions within adolescents' friendship networks may offer unique benefits not found with traditional programs that include random groupings of youth who are not familiar with each other. © The Author(s) 2012

The Benefits of a Friendship-Based HIV/STI Prevention Intervention for African American Youth

This article presents findings from a qualitative evaluation of an HIV/STI (sexually transmitted infection) prevention intervention for urban African American youth (Project ÒRÉ), which was delivered to groups of 3 to 8 adolescents who were members of the same friendship network. Sixteen focus groups (N = 63) were conducted with youth following their participation in the intervention. Results demonstrate high acceptability of the intervention. Both males and females revealed multiple benefits of attending the intervention with friends including feeling more comfortable, experiencing general satisfaction with the program, experiencing greater ease in talking and expressing self, being able to reveal sensitive information, and being able to relate to each other's experiences. Additional themes were presented only by males including feeling a sense of cohesion, the ability to protect each other from HIV/STIs in the future, and feeling safe. These results suggest that delivering HIV/STI and other prevention interventions within adolescents' friendship networks may offer unique benefits not found with traditional programs that include random groupings of youth who are not familiar with each other. © The Author(s) 2012