Faculty Bibliography

OBJECTIVES: This study was designed to evaluate the clinical and prognostic aspects of long QT syndrome (LQTS)-related cardiac events that occur in the first year of life (infancy). BACKGROUND: The clinical implications for patients with long QT syndrome who experience cardiac events in infancy have not been studied previously. METHODS: The study population of 3,323 patients with QT interval corrected for heart rate (QTc) > or =450 ms enrolled in the International LQTS Registry involved 20 patients with sudden cardiac death (SCD), 16 patients with aborted cardiac arrest (ACA), 34 patients with syncope, and 3,253 patients who were asymptomatic during the first year of life. RESULTS: The risk factors for a cardiac event among 212 patients who had an electrocardiogram recorded in the first year of life included QTc > or =500 ms, heart rate < or =100 beats/min, and female sex. An ACA before age 1 year was associated with a hazard ratio of 23.4 (p < 0.01) for ACA or SCD during ages 1 to 10 years. During the 10-year follow-up after infancy, beta-blocker therapy was associated with a significant reduction in ACA/SCD only in those with a syncopal episode within 2 years before ACA/SCD but not for those who survived ACA in infancy. CONCLUSIONS: Patients with LQTS who experience ACA during the first year of life are at very high risk for subsequent ACA or death during their next 10 years of life, and beta-blockers might not be effective in preventing fatal or near-fatal cardiac events in this small but high-risk subset

BACKGROUND: Identification of mutations in cardiac ion channel genes concurs to the diagnosis of long-QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. However, because availability of genetic screening is still limited and reimbursement policies are lacking, there is a need of evidence-based criteria to prioritize access to genetic testing for these diseases. METHODS AND RESULTS: We determined the yield of genetic testing and cost per positive genotyping in 1394 consecutive probands. Among the 546 patients referred for long-QT syndrome-genes screening, those with clinical diagnosis of long-QT syndrome had the highest yield (64%) and lowest cost (US $8418) for each positive genotyping. Among 798 individuals screened for mutation on the SCN5A gene, the highest yield was obtained in patients with type 1 Brugada syndrome ECG pattern (51 of 405; 13%) corresponding to a cost of US $21441 per positive genotyping. In conclusive Brugada syndrome patients the presence of atrioventricular block (odds ratio: 3.3, CI: 1.8 to 6.1; P=0.0001) increases the yield (23%) of genotyping and reduces its cost (US $ 11700). Among 175 patients screened on RyR2 gene, those with documented bidirectional ventricular tachycardia had the highest incidence (62%) of mutations and the lowest cost (US $5263) per positive genotyping. Genetic screening of unselected family members of sudden cardiac death victims and idiopathic ventricular fibrillation survivors is largely ineffective (yield of 9%) and costly (US $71430 per 1 positive genotyping). CONCLUSIONS: Genotyping can be performed at reasonable cost in individuals with conclusive diagnosis of long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia, and in patients with type I Brugada syndrome ECG with atrioventricular block. These patients should be given priority to access genetic testing

Cardiac ryanodine receptor (RyR2) mutations are associated with autosomal dominant catecholaminergic polymorphic ventricular tachycardia, suggesting that alterations in Ca(2+) handling underlie this disease. Here we analyze the underlying Ca(2+) release defect that leads to arrhythmia in cardiomyocytes isolated from heterozygous knock-in mice carrying the RyR2(R4496C) mutation. RyR2(R4496C-/-) littermates (wild type) were used as controls. [Ca(2+)](i) transients were obtained by field stimulation in fluo-3-loaded cardiomyocytes and viewed using confocal microscopy. In our basal recording conditions (2-Hz stimulation rate), [Ca(2+)](i) transients and sarcoplasmic reticulum Ca(2+) load were similar in wild-type and RyR2(R4496C) cells. However, paced RyR2(R4496C) ventricular myocytes presented abnormal Ca(2+) release during the diastolic period, viewed as Ca(2+) waves, consistent with the occurrence of delayed afterdepolarizations. The occurrence of this abnormal Ca(2+) release was enhanced at faster stimulation rates and by beta-adrenergic stimulation, which also induced triggered activity. Spontaneous Ca(2+) sparks were more frequent in RyR2(R4496C) myocytes, indicating increased RyR2(R4496C) activity. When permeabilized cells were exposed to different cytosolic [Ca(2+)](i), RyR2(R4496C) showed a dramatic increase in Ca(2+) sensitivity. Isoproterenol increased [Ca(2+)](i) transient amplitude and Ca(2+) spark frequency to the same extent in wild-type and RyR2(R4496C) cells, indicating that the beta-adrenergic sensitivity of RyR2(R4496C) cells remained unaltered. This effect was independent of protein expression variations because no difference was found in the total or phosphorylated RyR2 expression levels. In conclusion, the arrhythmogenic potential of the RyR2(R4496C) mutation is attributable to the increased Ca(2+) sensitivity of RyR2(R4496C), which induces diastolic Ca(2+) release and lowers the threshold for triggered activity

BACKGROUND: Beta-blocker efficacy in long-QT syndrome type 1 is good but variably reported, and the causes of cardiac events despite beta-blocker therapy have not been ascertained. METHODS AND RESULTS: This was a retrospective study of the details surrounding cardiac events in 216 genotyped long-QT syndrome type 1 patients treated with beta-blocker and followed up for a median time of 10 years. Before beta-blocker, cardiac events occurred in 157 patients (73%) at a median age of 9 years, with cardiac arrest (CA) in 26 (12%). QT-prolonging drugs were used by 17 patients; 9 of 17 (53%) had CA compared with 17 of 199 nonusers (8.5%; odds ratio, 12.0; 95% confidence interval, 4.1 to 35.3; P<0.001). After beta-blocker, 75% were asymptomatic, and cardiac events were significantly reduced (P<0.001), with a median event count (quartile 1 to 3) per person of 0 (0 to 1). Twelve patients (5.5%) suffered CA/sudden death, but 11 of 12 (92%) were noncompliant (n=8), were on a QT-prolonging drug (n=2), or both (n=1) at the time of the event. The risk for CA/sudden death in compliant patients not taking QT-prolonging drugs was dramatically less compared with noncompliant patients on QT-prolonging drugs (odds ratio, 0.03; 95% confidence interval, 0.003 to 0.22; P=0.001). None of the 26 patients with CA before beta-blocker had CA/sudden death on beta-blockers. CONCLUSIONS: beta-Blockers are extremely effective in long-QT syndrome type 1 and should be administered at diagnosis and ideally before the preteen years. beta-Blocker noncompliance and use of QT-prolonging drug are responsible for almost all life-threatening 'beta-blocker failures.' beta-Blockers are appropriate therapy for asymptomatic patients and those who have never had a CA or beta-blocker therapy. Routine implantation of cardiac defibrillators in such patients does not appear justified

Introduction: Brugada syndrome (BrS) is a heritable arrhythmogenic disease characterized by an augmented risk of sudden cardiac arrest (SCA). Studies on the pediatric population are few and on a limited number of patients. We describe the natural history of 90 children with BrS and on 48 genotyped patients with BrS, representing the largest series of child carriers of SCN5A mutations reported to date. Methods: 90 children (63 males) clinically and/or genetically affected by BrS, mean 10+/-6y, from 64 different families were studied using retrospective case review. Results: Type I or II ECG was observed in 40 patients (pts); 21 pts had ECG type I and 19 pts had ECG type II; 25 during protocol drug infusion and 5 with fever; 46 pts were studied because carriers of BrS mutations, despite normal ECG. Among the 21 patients with a spontaneous type I ECG, 4 were symptomatic (19%) and among the 19 patients with a spontaneous type II ECG, 5 were symptomatic (26%). 2/25, patients with a drug-induced phenotype were symptomatic (8%). Male predominance was observed in the symptomatic group (boys, 77%; girls, 30%). Family history of SCA was present in 35/90 pts. EP study, performed in 16 pts, was positive in only 1. ICD was implanted in 6 pts. During a mean follow-up of 50+/-34 months, 1 child experienced syncope; all other pts remained asymptomatic. Genetic screening for SCN5A was performed in 32 probands (pbs): 16 were carriers of a genetic defect. 57 pts were studied because of family history of BrS; 52 were carriers of the mutation found in their pbs, 5 belong to families with unknown genotype, but were clinically affected. Conclusions: In the pediatric population, ECG pattern and clinical manifestation of BrS are present in a small percentage of pts, suggesting a more subtle phenotype. Symptoms or ECG pattern can be precipitated by fever. Also, the role of EP study is not conclusive in pediatric BrS. In contrast to adults, some 50% of pediatric pbs are genetically affected, suggesting that a strict clinical selection of pts for SCN5A screening may lead to higher genotyping success

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by life threatening arrhythmias elicited by physical and emotional stress in young individuals. The recessive form of CPVT is associated with mutation in the cardiac calsequestrin gene (CASQ2). We engineered and characterized a homozygous CASQ2(R33Q/R33Q) mouse model that closely mimics the clinical phenotype of CPVT patients. CASQ2(R33Q/R33Q) mice develop bidirectional VT on exposure to environmental stress whereas CASQ2(R33Q/R33Q) myocytes show reduction of the sarcoplasmic reticulum (SR) calcium content, adrenergically mediated delayed (DADs) and early (EADs) afterdepolarizations leading to triggered activity. Furthermore triadin, junctin, and CASQ2-R33Q proteins are significantly decreased in knock-in mice despite normal levels of mRNA, whereas the ryanodine receptor (RyR2), calreticulin, phospholamban, and SERCA2a-ATPase are not changed. Trypsin digestion studies show increased susceptibility to proteolysis of mutant CASQ2. Despite normal histology, CASQ2(R33Q/R33Q) hearts display ultrastructural changes such as disarray of junctional electron-dense material, referable to CASQ2 polymers, dilatation of junctional SR, yet normal total SR volume. Based on the foregoings, we propose that the phenotype of the CASQ2(R33Q/R33Q) CPVT mouse model is portrayed by an unexpected set of abnormalities including (1) reduced CASQ2 content, possibly attributable to increased degradation of CASQ2-R33Q, (2) reduction of SR calcium content, (3) dilatation of junctional SR, and (4) impaired clustering of mutant CASQ2

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)

BACKGROUND: Previous studies that assessed the risk of life-threatening cardiac events in patients with congenital long-QT syndrome (LQTS) have focused mainly on the first 4 decades of life, whereas the clinical course of this inherited cardiac disorder in the older population has not been studied. METHODS AND RESULTS: The risk of aborted cardiac arrest or death from age 41 though 75 years was assessed in 2759 subjects from the International LQTS Registry, categorized into electrocardiographically affected (corrected QT interval [QTc] > or = 470 ms), borderline (QTc 440 to 469 ms), and unaffected (QTc < 440 ms) subgroups. The affected versus unaffected adjusted hazard ratio for aborted cardiac arrest or death was 2.65 (P<0.001) in the age range of 41 to 60 years and 1.23 (P=0.31) in the age range of 61 to 75 years. The clinical course of study subjects displayed gender differences: Affected LQTS women experienced a significantly higher cumulative event rate (26%) than borderline (16%) and unaffected (12%) women (P=0.001), whereas event rates were similar among the 3 respective subgroups of men (29%, 26%, and 27%; P=0.16). Recent syncope (< 2 years in the past) was the predominant risk factor in affected subjects (hazard ratio 9.92, P<0.001), and the LQT3 genotype was identified as the most powerful predictor of outcome in a subset of 871 study subjects who were genetically tested for a known LQTS mutation (hazard ratio 4.76, P=0.02). CONCLUSIONS: LQTS subjects maintain a high risk for life-threatening cardiac events after age 40 years. The phenotypic expression of affected subjects is influenced by age-specific factors related to gender, clinical history, and the LQTS genotype