Prevalence and associated factors of ECG abnormality patterns indicative of cardiac channelopathies among adult general population of Tehran, Iran: a report from the Tehran Cohort Study (TeCS).

BACKGROUND: The characteristics of electrocardiogram (ECG) abnormalities related to cardiac channelopathies potentially linked to sudden cardiac death (SCD) are not widely recognized in Iran. We examined the prevalence of such ECG patterns and their related factors among adult residents of Tehran, Iran. METHODS: The clinical characteristics and 12-lead ECGs of Tehran Cohort Study participants were examined. Long QT intervals, short QT intervals, Brugada syndrome (BrS) patterns, and early repolarization (ER) were evaluated using computer-based assessment software validated by cardiologists. Logistic regression models were employed to identify the factors associated with the prevalence of different ECG patterns. RESULTS: Out of 7678 available ECGs, 7350 were included in this analysis. Long QT interval, ER pattern, BrS patterns, and short QT interval were found in 3.08%, 1.43%, 0.31%, and 0.03% of participants, respectively. The prevalence of long QT interval increased with age, opium consumption, and presence of hypertension. Younger age, lower body mass index (BMI), alcohol use and male sex were independently linked to an elevated prevalence of ER pattern. Most individuals with BrS patterns were men (95%) and had lower BMI, high- and low-density lipoprotein, and total cholesterol compared to those without the BrS pattern. At a mean follow-up of 30.2 ± 5.5 months, all-cause mortality in the group exhibiting abnormal ECG patterns (6.3%) was approximately twice as high as that in the group without such patterns (2.96%). CONCLUSION: Abnormal ECG patterns corresponding to channelopathies were relatively rare among adult residents of the Tehran population, and their prevalence was influenced by various factors. CLINICAL TRIAL NUMBER: Not applicable.

Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome.

BACKGROUND: Implicit in the genetic evaluation of patients with suspected genetic diseases is the assumption that the genes evaluated are causative for the disease based on robust scientific and statistical evidence. However, in the past 20 years, considerable variability has existed in the study design and quality of evidence supporting reported gene-disease associations, raising concerns of the validity of many published disease-causing genes. Brugada syndrome (BrS) is an arrhythmia syndrome with a risk of sudden death. More than 20 genes have been reported to cause BrS and are assessed routinely on genetic testing panels in the absence of a systematic, evidence-based evaluation of the evidence supporting the causality of these genes. METHODS: We evaluated the clinical validity of genes tested by diagnostic laboratories for BrS by assembling 3 gene curation teams. Using an evidence-based semiquantitative scoring system of genetic and experimental evidence for gene-disease associations, curation teams independently classified genes as demonstrating limited, moderate, strong, or definitive evidence for disease causation in BrS. The classification of curator teams was reviewed by a clinical domain expert panel that could modify the classifications based on their independent review and consensus. RESULTS: Of 21 genes curated for clinical validity, biocurators classified only 1 gene ( SCN5A) as definitive evidence, whereas all other genes were classified as limited evidence. After comprehensive review by the clinical domain Expert panel, all 20 genes classified as limited evidence were reclassified as disputed with regard to any assertions of disease causality for BrS. CONCLUSIONS: Our results contest the clinical validity of all but 1 gene clinically tested and reported to be associated with BrS. These findings warrant a systematic, evidence-based evaluation for reported gene-disease associations before use in patient care.

The landscape of epilepsy-related GATOR1 variants.

PURPOSE: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. RESULTS: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. CONCLUSION: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

First-degree atrioventricular block on basal electrocardiogram predicts future arrhythmic events in patients with Brugada syndrome: a long-term follow-up study from the Veneto region of Northeastern Italy.

AIMS: This study was designed to assess the prognostic value of clinical and electrocardiographic parameters in Brugada syndrome (BrS). METHODS AND RESULTS: The study population included 272 consecutive patients (82% males; mean age 43 ± 12 years), with either a spontaneous (n = 137, 50%) or drug-induced (n = 135, 50%) Type 1 Brugada electrocardiogram (ECG) pattern. The study combined endpoint included sudden cardiac death (SCD), cardiac arrest, and appropriate intervention of implantable cardioverter-defibrillator (ICD). A first-degree atrioventricular (AV) block (PR = 219 ± 17 ms) was documented at basal ECG in 45 patients (16.5%); 27 of these underwent an electrophysiological study with recording in 21 (78%) of an HV interval ≥55 ms (mean 61 ± 3 ms). Patients with first-degree AV block had a wider QRS complex (median 110 ms vs. 95 ms; P = 0.04) and more often showed a left anterior hemiblock pattern (n = 13, 29% vs. n = 35, 16%; P = 0.056). During a mean follow-up of 85 ± 55 months, 17 patients (6.3%) experienced ≥1 major arrhythmic events (appropriate ICD intervention, n = 13 and SCD, n = 4). At univariate analysis, the occurrence of major arrhythmic events was significantly associated with a history of syncope or cardiac arrest (P < 0.001), Type 1 ECG pattern (P = 0.04), and first-degree AV block (P < 0.001). Univariate and multivariable predictors of events included a history of syncope or cardiac arrest [hazard ratio (HR) 5.8, 95% confidence interval (95% CI) 2.04-16.5; P < 0.001; and HR 6.68, 95% CI 2.34-19.1; P < 0.001; respectively], a spontaneous Type 1 ECG pattern (HR 1.56, 95% CI 1.03-4.24; P = 0.033; and HR 1.84, 95% CI 1.01-4.29; P = 0.044; respectively) and a first-degree AV block at baseline ECG (HR 3.84, 95% CI 1.47-9.99; P = 0.006; and HR 4.65, 95% CI 2.34-19.1; P = 0.002; respectively). CONCLUSION: Besides a history of cardiac arrest or syncope, first-degree AV block on basal ECG is an independent predictor of malignant arrhythmic events and a stronger marker of arrhythmic risk than a spontaneous 'coved-type' ECG pattern in patients with BrS.

A meta-analysis on the prognostic significance of inferolateral early repolarization pattern in Brugada syndrome.

Aims: The early repolarization (ER) pattern has been linked to an increased risk for arrhythmic death in various clinical settings. There are limited and conflicting data regarding the prognostic significance of ER pattern in Brugada syndrome (BS). The aim of this meta-analysis was to provide a detailed analysis of the currently available studies regarding the arrhythmic risk in patients with BS and ER pattern. Methods and results: Current databases were searched until May 2015. A random-effect meta-analysis of the effect of ER pattern on the incidence of arrhythmic events in patients with BS was performed. Five studies were included comprising a total of 1375 patients with BS. An ER pattern was reported in 177 patients (12.8%). During follow-up (44.9-93 months), 143 patients (10.4%) suffered an arrhythmic event. Overall, BS patients with ER pattern displayed an increased risk of arrhythmic events compared to patients without ER (OR 3.29, 95% CI: 2.06 to 5.26, P < 0.00001; Heterogeneity: P = 0.11, I2 = 48%). Three studies provided data regarding ER pattern location. Inferior, lateral, or inferolateral ER pattern location was observed in 20.3%, 32.2%, and 48%, respectively. An inferolateral ER location conferred the higher arrhythmic risk (OR 4.87, 95% CI: 2.64 to 9.01, P< 0.00001; Heterogeneity: P = 0.85, I2 = 0%). Conclusion: This meta-analysis suggests that the ER pattern is associated with a high risk of arrhythmic events in patients with BS. In particular, BS patients with inferolateral ER (global ER pattern) displayed the highest arrhythmic risk.

Clinical outcome of patients with the Brugada type 1 electrocardiogram without prophylactic implantable cardioverter defibrillator in primary prevention: a cumulative analysis of seven large prospective studies.

Aims: Patients with the Brugada type 1 ECG (Br type 1) without previous aborted sudden death (aSD) who do not have a prophylactic ICD constitute a very large population whose outcome is little known. The objective of this study was to evaluate the risk of SD or aborted SD (aSD) in these patients. Methods and results: We conducted a meta-analysis and cumulative analysis of seven large prospective studies involving 1568 patients who had not received a prophylactic ICD in primary prevention. Patients proved to be heterogeneous. Many were theoretically at low risk, in that they had a drug-induced Br type 1 (48%) and/or were asymptomatic (87%), Others, in contrast, had one or more risk factors. During a mean/median follow-up ranging from 30 to 48 months, 23 patients suffered SD and 1 had aSD. The annual incidence of SD/aSD was 0.5% in the total population, 0.9% in patients with spontaneous Br type 1 and 0.08% in those with drug-induced Br type 1 (P = 0.0001). The paper by Brugada et al. reported an incidence of SD more than six times higher than the other studies, probably as a result of selection bias. On excluding this paper, the annual incidence of SD/aSD in the remaining 1198 patients fell to 0.22% in the total population and to 0.38 and 0.06% in spontaneous and drug-induced Br type 1, respectively. Of the 24 patients with SD/aSD, 96% were males, the mean age was 39 ± 15 years, 92% had spontaneous Br type 1, 61% had familial SD (f-SD), and only 18.2% had a previous syncope; 43% had a positive electrophysiological study. Multiple meta-analysis of individual trials showed that spontaneous Br type 1, f-SD, and previous syncope increased the risk of SD/aSD (RR 2.83, 2.49, and 3.03, respectively). However, each of these three risk factors had a very low positive predictive value (PPV) (1.9-3.3%), while negative predictive values (NPV) were high (98.5-99.7%). The incidence of SD/aSD was only slightly higher in patients with syncope than in asymptomatic patients (2% vs. 1.5%, P = 0.6124). Patients with SD/aSD when compared with the others had a mean of 1.74 vs. 0.95 risk factors (P = 0.026). Conclusion: (i) In patients with Br type 1 ECG without an ICD in primary prevention, the risk of SD/aSD is low, particularly in those with drug-induced Br type 1; (ii) spontaneous Br type 1, f-SD, and syncope increase the risk. However, each of these risk factors individually has limited clinical usefulness, owing to their very low PPV; (iii) patients at highest risk are those with more than one risk factor.

Unsafe Drug Use and Arrhythmic Events in Brugada Patients with ICD: Results of a Long-Term Follow-Up.

PURPOSE: Brugada syndrome is a hereditary disease linked with an increased risk of sudden death that may require an implantable cardioverter-defibrillator (ICD) in order to halt the arrhythmic events. The aim of this study was to identify possible triggers for appropriate ICD therapies in patients with Brugada syndrome, focusing on their past and current therapeutic profiles. METHODS: Thirty patients with high-risk Brugada syndrome, with ICD implanted at the Coimbra Hospital and University Center, were enrolled. Patients were questioned about their Brugada syndrome history, previous cardiac events, comorbidities, present and past medications, and physical activity. Patients were followed up during 5.8 ± 5.3 years. The ICD was interrogated, and arrhythmic events and device therapies were recorded. The cohort who received appropriate ICD therapies was compared with the remaining patients to determine the potential link between clinical variables and potentially fatal arrhythmic events. RESULTS: More than half of the patients (53.3%) took at least one non-recommended drug, and 16.7% received appropriate ICD therapies, with a long-term rate of 4.0%/year. There was a tendency for more appropriate ICD therapies in patients who took unsafe drugs (85.7 versus 45.5%, p = 0.062), and the mean time between unsafe drug intake and appropriate ICD therapies was 3.8 ± 7.5 days. CONCLUSIONS: This study revealed that the medical community is still unaware of the pharmacological restrictions imposed by Brugada syndrome. Patients who took non-recommended drugs seem to have a higher risk of ventricular arrhythmic events.

IDENTIFYING NEW SUDDEN DEATH GENES.

Inherited conditions that lead to cardiac arrhythmias and sudden cardiac death remain an important cause of morbidity and mortality. Identifying the genes responsible for these rare conditions can provide insights into the more common and heritable forms of sudden cardiac death seen in patients with structural heart disease. We and others have used candidate gene approaches and positional cloning in large families to show that mutations in ion channels and ion channel related proteins cause familial arrhythmia syndromes including long QT and Brugada syndromes. The genes responsible for many familial arrhythmia syndromes and the vast majority of the predisposition to common arrhythmias remain unknown. Using whole exome sequencing in families with Brugada syndrome and idiopathic ventricular fibrillation, we now seek to identify mutations in genes previously not thought to play a significant role in the heart.

A score model to predict risk of events in patients with Brugada Syndrome.

AIMS: Risk stratification in Brugada Syndrome (BS) remains challenging. Arrhythmic events can occur life-long and studies with long follow-ups are sparse. The aim of our study was to investigate long-term prognosis and risk stratification of BS patients. METHODS AND RESULTS: A single centre consecutive cohort of 400 BS patients was included and analysed. Mean age was 41.1 years, 78 patients (19.5%) had a spontaneous type I electrocardiogram (ECG). Clinical presentation was aborted sudden cardiac death (SCD) in 20 patients (5.0%), syncope in 111 (27.8%) and asymptomatic in 269 (67.3%). Familial antecedents of SCD were found in 184 individuals (46.0%), in 31 (7.8%) occurred in first-degree relatives younger than 35 years. An implantable cardioverter defibrillator (ICD) was placed in 176 (44.0%). During a mean follow-up of 80.7 months, 34 arrhythmic events occurred (event rate: 1.4% year). Variables significantly associated to events were: presentation as aborted SCD (Hazard risk [HR] 20.0), syncope (HR 3.7), spontaneous type I (HR 2.7), male gender (HR 2.7), early SCD in first-degree relatives (HR 2.9), SND (HR 5.0), inducible VA (HR 4.7) and proband status (HR 2.1). A score including ECG pattern, early familial SCD antecedents, inducible electrophysiological study, presentation as syncope or as aborted SCD and SND had a predictive performance of 0.82. A score greater than 2 conferred a 5-year event probability of 9.2%. CONCLUSIONS: BS patients remain at risk many years after diagnosis. Early SCD in first-degree relatives and SND are risk factors for arrhythmic events. A simple risk score might help in the stratification and management of BS patients.

Numerous Brugada syndrome-associated genetic variants have no effect on J-point elevation, syncope susceptibility, malignant cardiac arrhythmia, and all-cause mortality.

PURPOSE: We investigated whether Brugada syndrome (BrS)-associated variants identified in the general population have an effect on J-point elevation as well as whether carriers of BrS variants were more prone to experience syncope and malignant ventricular arrhythmia and had increased mortality compared with noncarriers. METHODS: All BrS-associated variants were identified using the Human Gene Mutation Database (HGMD). Individuals were randomly selected from a general population study using whole-exome sequencing data (n = 870) and genotype array data (n = 6,161) and screened for BrS-associated variants. Electrocardiograms (ECG) were analyzed electronically, and data on syncope, ventricular arrhythmias, and mortality were obtained from administrative health-care registries. RESULTS: In HGMD, 382 BrS-associated genetic variants were identified. Of these, 28 variants were identified in the study cohort. None of the carriers presented with type 1 BrS ECG pattern. Mean J-point elevation in V1 and V2 were within normal guideline limits for carriers and noncarriers. There was no difference in syncope susceptibility (carriers 8/624; noncarriers 98/5,562; P = 0.51), ventricular arrhythmia (carriers 4/620; noncarriers 9/5,524; P = 0.24), or overall mortality (hazard ratio 0.93, 95% CI 0.63-1.4). CONCLUSIONS: Our data indicate that a significant number of BrS-associated variants are not the monogenic cause of BrS.Genet Med advance online publication 06 October 2016.

The Utility of Exercise Testing in Risk Stratification of Asymptomatic Patients With Type 1 Brugada Pattern.

INTRODUCTION: Risk stratification of asymptomatic patients with a Brugada type 1 ECG pattern remains an unresolved clinical conundrum. In contrast to provocative pharmacological testing in Brugada syndrome, there is limited data on the role of exercise stress testing as a risk stratification modality. The objective of this study was to evaluate the utility of exercise testing in asymptomatic patients with type 1 Brugada pattern to prognosticate major arrhythmic events (MAE) during follow-up. METHODS AND RESULTS: Treadmill exercise testing was conducted for 75 asymptomatic patients with type 1 Brugada pattern and for 88 healthy control subjects. The clinical end point of MAE was defined as the occurrence of sudden cardiac death (SCD) or resuscitated ventricular fibrillation (VF). During a follow-up of 77.9 ± 28.9 months, eight MAE occurred (five VF and three SCD). Multivariate Cox regression analysis showed that the following were independent predictors of MAE in asymptomatic patients with a type 1 Brugada pattern: increase in S wave upslope duration ratio >30% at peak exercise (HR 1.35, 95% CI 1.08-10.97, P = 0.023), augmentation of J point elevation in lead aVR >2 mm in late recovery (HR 1.88, 95% 1.21-15.67, P = 0.011), and delayed HR recovery (HR 1.14, 95% CI 1.06-18.22, P = 0.042). A high-risk cohort was identified by the final step-wise regression model with good accuracy (specificity = 98.4%, sensitivity = 62.5%) and discriminative power (AUC = 0.93, 95% CI 0.89-0.96, P = 0.002). Kaplan-Meier analysis revealed increasing MAE in subjects with one, two, or three predictors, respectively (log rank P < 0.001). CONCLUSIONS: Exercise testing in asymptomatic patients with type 1 Brugada pattern aids in identification of high-risk patients and provides a unique window of opportunity for early intervention.

Clinical Significance of ST Elevation in Lead aVR in Acute Pulmonary Embolism.

BACKGROUND: Prognostic stratification of patients with acute pulmonary embolism (PTE) is crucial in identifying patients who would benefit from more aggressive treatment. We aimed to examine the value of ST elevation in lead aVR (STEaVR ) in predicting hospital mortality following PTE. MATERIALS: Two hundred patients with a diagnosis of PTE were allocated into two groups based on the presence or absence of STEaVR . Multivariate logistic regression analysis was used to investigate the role of "STEaVR " in relation to the other risk factors in predicting prognosis of PTE. RESULTS: Out of 200 patients, 24 (12.0%) had STEaVR . Patients with STEaVR were more likely to present with hypotension and tachycardia than those who did not have this electrocardiographic finding. A total of 33.3% of patients with STEaVR and 13.1% of those without STEaVR died during hospitalization. STEaVR had a low sensitivity of 25.8% but a high specificity of 90.5% for predicting hospital mortality. Odds ratio for hospital mortality was 3.32 for STEaVR with 95% confidence interval of 1.28-8.64 (P = 0.017) in univariate analysis. In multivariate analysis shock was the strongest predictor of hospital mortality. CONCLUSION: The presence of STEaVR is indicative of hemodynamic instability, thereby having the ability to predict poor outcome. However, its impact on hospital mortality disappears when the presence of shock on admission is factored in the prediction model.

Clinical impact of myocardial mTORC1 activation in nonischemic dilated cardiomyopathy.

BACKGROUND: Activity of mTOR complex 1 (mTORC1) has been shown to be up-regulated in animal models of heart failure. Here, we investigated the change and role of mTORC1 in human nonischemic dilated cardiomyopathy (NICM). METHODS: Endomyocardial biopsy specimens were obtained from patients with NICM (n=52) and from Brugada syndrome patients with normal LVEF as controls (n=10). The specimens were stained for phospho-ribosomal protein S6 (p-Rps6) and phospho-p70S6K (p-p70S6K), and the area with p-Rps6 signal was used as an index of mTORC1 activity. Using median mTORC1 activity, patients were divided into a high mTORC1 activity (H-mTOR) group and a low mTORC1 activity (L-mTOR) group. RESULTS: The ratio of p-Rps6-positive area in biopsy samples was 10-fold larger in patients with NICM than in controls (2.0±2.2% vs. 0.2±0.2%, p<0.01). p-p70S6K signal level was higher in the H-mTOR group than in the L-mTOR group. The proportion of patients with a family history of cardiomyopathy was higher and the proportion of patients on ACE inhibitors or angiotensin receptor blockers was lower in the H-mTOR group than in the L-mTOR group. The p-Rps6-positive area was correlated with extent of myocardial fibrosis (r=0.46, p<0.01). The cardiac event-free survival rate during a 5-year follow-up period tended to be lower in the H-mTOR group than in the L-mTOR group (52.9% vs. 81.6%, P=0.10). CONCLUSION: Aberrant activation of mTORC1 in cardiomyocytes was associated with myocardial fibrosis and a trend for worse prognosis in patients with NICM, indicating that persistently activated mTORC1 contributes to progression of human heart failure.

Mosaic mutations in early-onset genetic diseases.

PURPOSE: An emerging approach in medical genetics is to identify de novo mutations in patients with severe early-onset genetic disease that are absent in population controls and in the patient's parents. This approach, however, frequently misses post-zygotic "mosaic" mutations that are present in only a portion of the healthy parents' cells and are transmitted to offspring. METHODS: We constructed a mosaic transmission screen for variants that have an ~50% alternative allele ratio in the proband but are significantly less than 50% in the transmitting parent. We applied it to two family-based genetic disease cohorts consisting of 9 cases of sudden unexplained death in childhood (SUDC) and 338 previously published cases of epileptic encephalopathy. RESULTS: The screen identified six parental-mosaic transmissions across the two cohorts. The resultant rate of ~0.02 identified transmissions per trio is far lower than that of de novo mutations. Among these transmissions were two likely disease-causing mutations: an SCN1A mutation transmitted to an SUDC proband and her sibling with Dravet syndrome, as well as an SLC6A1 mutation in a proband with epileptic encephalopathy. CONCLUSION: These results highlight explicit screening for mosaic mutations as an important complement to the established approach of screening for de novo mutations.Genet Med 18 7, 746-749.

Genetic and forensic implications in epilepsy and cardiac arrhythmias: a case series.

Epilepsy affects approximately 3% of the world's population, and sudden death is a significant cause of death in this population. Sudden unexpected death in epilepsy (SUDEP) accounts for up to 17% of all these cases, which increases the rate of sudden death by 24-fold as compared to the general population. The underlying mechanisms are still not elucidated, but recent studies suggest the possibility that a common genetic channelopathy might contribute to both epilepsy and cardiac disease to increase the incidence of death via a lethal cardiac arrhythmia. We performed genetic testing in a large cohort of individuals with epilepsy and cardiac conduction disorders in order to identify genetic mutations that could play a role in the mechanism of sudden death. Putative pathogenic disease-causing mutations in genes encoding cardiac ion channel were detected in 24% of unrelated individuals with epilepsy. Segregation analysis through genetic screening of the available family members and functional studies are crucial tasks to understand and to prove the possible pathogenicity of the variant, but in our cohort, only two families were available. Despite further research should be performed to clarify the mechanism of coexistence of both clinical conditions, genetic analysis, applied also in post-mortem setting, could be very useful to identify genetic factors that predispose epileptic patients to sudden death, helping to prevent sudden death in patients with epilepsy.

Prevalence and prognosis of Brugada electrocardiogram patterns in an elderly Han Chinese population: a nation-wide community-based study (HALST cohort).

AIMS: The exact world-wide prevalence of Brugada electrocardiogram (ECG) pattern is still unclear, especially in adults aged 55 years and older. METHODS AND RESULTS: The study was conducted as part of the Healthy Aging Longitudinal Study in Taiwan (HALST). Using a stratified random sampled method, a sample of community-dwelling subjects was recruited from seven community-based regions across Taiwan. All enrolled subjects were follow-up annually and cause of death was documented by citizen death records. A total of 5214 subjects were enrolled (male/female: 2530/2684) with a mean age of 69 ± 8 years. The overall prevalence of Brugada ECG patterns was 3.32%. Four subjects carried spontaneous Type 1 Brugada ECG pattern, 68 carried Type 2, and 101 carried Type 3. Compared with the world-wide average prevalence of Brugada ECG patterns, the prevalence of spontaneous Type 1 Brugada ECG pattern in subjects from the HALST cohort was similar (0.077 vs. 0.07%) and the combined prevalence of Types 2 and 3 Brugada ECG pattern was 10 times higher (3.24 vs. 0.28%) even the mean age of study subjects was significantly higher (69 ± 8 vs. 35 ± 8, P < 0.001). However, all-cause mortality and cardiac mortality rates were not significantly different between subjects with and without Brugada ECG patterns during the 4-year follow-up (log-rank test, P = 0.21, 0.32, respectively). CONCLUSION: The prevalence of Brugada ECG pattern in adults aged 55 years and older in Taiwan was higher than the average world-wide prevalence but was not associated with increased mortality.

Contribution of Cardiac Sodium Channel ß-Subunit Variants to Brugada Syndrome.

BACKGROUND: Brugada syndrome (BrS) is an inheritable cardiac disease associated with syncope, malignant ventricular arrhythmias and sudden cardiac death. The largest proportion of mutations in BrS is found in the SCN5A gene encoding the α-subunit of cardiac sodium channels (Nav1.5). Causal SCN5A mutations are present in 18-30% of BrS patients. The additional genetic diagnostic yield of variants in cardiac sodium channel ß-subunits in BrS patients was explored and functional studies on 3 novel candidate variants were performed. METHODS AND RESULTS: TheSCN1B-SCN4B genes were screened, which encode the 5 sodium channel ß-subunits, in a SCN5A negative BrS population (n=74). Five novel variants were detected; in silico pathogenicity prediction classified 4 variants as possibly disease causing. Three variants were selected for functional study. These variants caused only limited alterations of Nav1.5 function. Next generation sequencing of a panel of 88 arrhythmia genes could not identify other major causal mutations. CONCLUSIONS: It was hypothesized that the studied variants are not the primary cause of BrS in these patients. However, because small functional effects of these ß-subunit variants can be discriminated, they might contribute to the BrS phenotype and be considered a risk factor. The existence of these risk factors can give an explanation to the reduced penetrance and variable expressivity seen in this syndrome. We therefore recommend including the SCN1-4B genes in a next generation sequencing-based gene panel.

Phenotype of Children with QT Prolongation Identified Using an Institution-Wide QT Alert System.

QT prolongation is an independent risk factor for cardiovascular mortality in adults. However, there is little information available on pediatric patients with QT prolongation and their outcomes. Herein, we evaluated the prevalence of QT prolongation in pediatric patients identified by an institution-wide QT alert system, and the spectrum of their phenotype. Patients with documented QT prolongation on an ECG obtained between November 2010 and June 2011 were included. There were 1303 pediatric ECGs, and 68 children had electrographically isolated QT prolongation. Comprehensive review of medical records was performed with particular attention to QT-prolonging clinical, laboratory, and medication data, which were summarized into a pro-QTc score. Overall, 68 (5 %) pediatric patients had isolated QT prolongation. The mean age of this pediatric cohort was 9 ± 6 years, and the average QTc was 494 ± 42 ms. All children had 1 or more QT-prolonging risk factor(s), most commonly QT-prolonging medications. One patient was identified with congenital long QT syndrome (LQTS), which was not previously diagnosed. In one-year follow-up, only one pediatric death (non-cardiac) occurred (1.5 %). Potentially QT-offending/pro-arrhythmic medications were changed in 80 % of pediatric patients after the physician received the QT alert. Children with QT prolongation had very low mortality and minimal polypharmacy. Still, medications and other modifiable conditions were the most common causes of QT prolongation. Children with a prolonged QTc should be evaluated for modifiable QT-prolonging factors. However, if no risk factors are present or the QTc does not attenuate after risk factor modification/removal, the child should be evaluated for congenital LQTS.

Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study-part 2.

BACKGROUND: Implantable cardioverter-defibrillator indications in Brugada syndrome remain controversial, especially in asymptomatic patients. Previous outcome data are limited by relatively small numbers of patients or short follow-up durations. We report the outcome of patients with Brugada syndrome implanted with an implantable cardioverter-defibrillator in a large multicenter registry. METHODS AND RESULTS: A total of 378 patients (310 male; age, 46±13 years) with a type 1 Brugada ECG pattern implanted with an implantable cardioverter-defibrillator (31 for aborted sudden cardiac arrest, 181 for syncope, and 166 asymptomatic) were included. Fifteen patients (4%) were lost to follow-up. During a mean follow-up of 77±42 months, 7 patients (2%) died (1 as a result of an inappropriate shock), and 46 patients (12%) had appropriate device therapy (5±5 shocks per patient). Appropriate device therapy rates at 10 years were 48% for patients whose implantable cardioverter-defibrillator indication was aborted sudden cardiac arrest, 19% for those whose indication was syncope, and 12% for the patients who were asymptomatic at implantation. At 10 years, rates of inappropriate shock and lead failure were 37% and 29%, respectively. Inappropriate shock occurred in 91 patients (24%; 4±4 shocks per patient) because of lead failure (n=38), supraventricular tachycardia (n=20), T-wave oversensing (n=14), or sinus tachycardia (n=12). Importantly, introduction of remote monitoring, programming a high single ventricular fibrillation zone (>210-220 bpm), and a long detection time were associated with a reduced risk of inappropriate shock. CONCLUSIONS: Appropriate therapies are more prevalent in symptomatic Brugada syndrome patients but are not insignificant in asymptomatic patients (1%/y). Optimal implantable cardioverter-defibrillator programming and follow-up dramatically reduce inappropriate shock. However, lead failure remains a major problem in this population.