Sudden Cardiac Arrest and Rare Genetic Variants in the Community.

BACKGROUND: Sudden cardiac arrest (SCA) ranks among the most common causes of death worldwide. Because SCA is most often lethal, yet mostly occurs in individuals without previously known cardiac disease, the identification of patients at risk for SCA could save many lives. In unselected SCA victims from the community, common genetic variants (which are not disease-causing per se, but may increase susceptibility to ventricular fibrillation) are found to be associated with increased SCA risk. However, whether rare genetic variants contribute to SCA risk in the community is largely unexplored. METHODS AND RESULTS: We here investigated the involvement of rare genetic variants in SCA risk at the population level by studying the prevalence of 6 founder genetic variants present in the Dutch population (PLN-p.Arg14del, MYBPC3-p.Trp792fsX17, MYBPC3-p.Arg943X, MYBPC3-p.Pro955fsX95, PKP2-p.Arg79X, and the Chr7q36 idiopathic ventricular fibrillation risk haplotype) in a cohort of 1440 unselected Dutch SCA victims included in the Amsterdam Resuscitation Study (ARREST). The six studied founder mutations were found to be more prevalent (1.1%) in the ARREST SCA cohort compared with an ethnically and geographically matched set of controls (0.4%, n=1379; P<0.05) or a set of Dutch individuals drawn from the Genome of the Netherlands (GoNL) study (0%, n=500; P<0.02). CONCLUSIONS: This finding provides proof-of-concept for the notion that rare genetic variants contribute to some extent to SCA risk in the community.

Improving usual care after sudden death in the young with focus on inherited cardiac diseases (the CAREFUL study): a community-based intervention study.

AIMS: Inherited cardiac diseases play an important role in sudden death (SD) in the young. Autopsy and cardiogenetic evaluation of relatives of young SD victims identifies relatives at risk. We studied the usual care after SD in the young aimed at identifying inherited cardiac disease, and assessed the efficacy of two interventions to improve this usual care. METHODS AND RESULTS: We conducted a community-based intervention study to increase autopsy rates of young SD victims aged 1-44 years and referral of their relatives to cardiogenetic clinics. In the Amsterdam study region, a 24/7 central telephone number and a website were available to inform general practitioners and coroners. In the Utrecht study region, they were informed by a letter and educational meetings. In two control regions usual care was monitored. Autopsy was performed in 169 of 390 registered SD cases (43.3%). Cardiogenetic evaluation of relatives was indicated in 296 of 390 cases (75.9%), but only 25 of 296 families (8.4%) attended a cardiogenetics clinic. Autopsy rates were 38.7% in the Amsterdam study region, 45.5% in the Utrecht study region, and 49.0% in the control regions. The proportion of families evaluated at cardiogenetics clinics in the Amsterdam study region, the Utrecht study region, and the control regions was 7.3, 9.9, and 8.8%, respectively. CONCLUSIONS: The autopsy rate in young SD cases in the Netherlands is low and few families undergo cardiogenetic evaluation to detect inherited cardiac diseases. Two different interventions did not improve this suboptimal situation substantially.

Sudden cardiac arrest in people with epilepsy in the community: Circumstances and risk factors.

OBJECTIVE: To ascertain whether characteristics of ventricular tachycardia/fibrillation (VT/VF) differed between people with epilepsy and those without and which individuals with epilepsy were at highest risk. METHODS: We ascertained 18 people with active epilepsy identified in a community-based registry of sudden cardiac arrest (SCA) with ECG-confirmed VT/VF (cases). We compared them with 470 individuals with VT/VF without epilepsy (VT/VF controls) and 54 individuals with epilepsy without VT/VF (epilepsy controls). Data on comorbidity, epilepsy severity, and medication use were collected and entered into (conditional) logistic regression models to identify determinants of VT/VF in epilepsy. RESULTS: In most cases, there was an obvious (10/18) or presumed cardiovascular cause (5/18) in view of preexisting heart disease. In 2 of the 3 remaining events, near-sudden unexpected death in epilepsy (SUDEP) was established after successful resuscitation. Cases had a higher prevalence of congenital/inherited heart disease (17% vs 1%, p = 0.002), and experienced VT/VF at younger age (57 vs 64 years, p = 0.023) than VT/VF controls. VT/VF in cases occurred more frequently at/near home (89% vs 58%, p = 0.009), and was less frequently witnessed (72% vs 89%, p = 0.048) than in VT/VF controls. Cases more frequently had clinically relevant heart disease (50% vs 15%, p = 0.005) and intellectual disability (28% vs 1%, p < 0.001) than epilepsy controls. CONCLUSION: Cardiovascular disease rather than epilepsy characteristics is the main determinant of VT/VF in people with epilepsy in the community. SCA and SUDEP are partially overlapping disease entities.

Reduced pre-hospital and in-hospital survival rates after out-of-hospital cardiac arrest of patients with type-2 diabetes mellitus: an observational prospective community-based study.

AIMS: Out-of-hospital cardiac arrest (OHCA) remains a major cause of death. We aimed to determine whether type-2 diabetes mellitus (T2DM) is associated with reduced pre-hospital and in-hospital survival rates after OHCA. METHODS AND RESULTS: An observational community-based cohort study was performed among 1549 OHCA patients with ECG-documented ventricular tachycardia/ventricular fibrillation (VT/VF). We compared pre-hospital and in-hospital survival rates between T2DM patients and non-diabetic patients. Analyses among T2DM patients were stratified according to current T2DM treatment, used as proxy for T2DM severity. Proportions of neurologically intact survival were analysed. Pre-hospital survival rates were lower in T2DM patients (n = 275) than in non-diabetic patients (n = 1274); 48.7 vs. 55.8% (univariate P = 0.032). Type-2 diabetes mellitus was associated with lower pre-hospital survival [OR 0.75 (0.58-0.98); after evaluation of the risk factors, we found no relevant confounding]. Patients treated with insulin only had lower pre-hospital survival rates than patients treated with oral glucose-lowering drugs only (37.3 vs. 53.3%, univariate P = 0.034), partially explained by location of OHCA and EMS response time [ORadj 0.62 (0.33-1.17)]. In-hospital survival rates were also lower in T2DM patients (n = 134) than in non-diabetic patients (n = 711); 40.3 vs. 57.7%, univariate P < 0.001. In those patients whose cause of OHCA was retrieved (n = 771), T2DM was significantly associated with lower in-hospital survival [ORadj 0.57 (0.37-0.87)]. Neurologically intact status at discharge was similarly high among T2DM and non-diabetic patients (94.4 vs. 94.6%, P = 0.954). CONCLUSION: T2DM is associated with lower pre-hospital and in-hospital survival rates after OHCA. Neurologically intact status at hospital discharge is high both among T2DM and non-diabetic patients.

Sudden cardiac death is associated both with epilepsy and with use of antiepileptic medications.

OBJECTIVE: Epilepsy is associated with increased risk for sudden cardiac death (SCD). We aimed to establish, in a community based study, whether this association is mediated by epilepsy per se, use of antiepileptic medications (AEMs), or both. METHODS: We studied SCD cases and age/sex matched controls in a case-control study in a large scale general practitioners' research database (n=478 661 patients). SCD risk for symptomatic epilepsy (seizure <2 years before SCD), stable epilepsy (no seizure <2 years before SCD), and use of AEMs (any indication) was determined. RESULTS: We identified 926 SCD cases and 9832 controls. Fourteen cases had epilepsy. Epilepsy was associated with an increased SCD risk (cases 1.5%, controls 0.5%; adjusted OR 2.8, 95% CI 1.4 to 5.3). SCD risk was increased for symptomatic epilepsy (cases 0.9%, controls 0.1%; adjusted OR 5.8, 95% CI 2.1 to 15.6), but not with stable epilepsy (cases 0.6%, controls 0.4%; adjusted OR 1.6, 95% CI 0.7 to 4.1). AEM use was found in 23 cases and was associated with an increased SCD risk (cases 2.5%, controls 0.8%; adjusted OR overall 2.6, 95% CI 1.5 to 4.3) among symptomatic epilepsy cases (cases 0.9%, controls 0.1%; adjusted OR 6.4, 95% CI 2.4 to 17.4) and non-epilepsy cases (cases 1.0%, controls 0.4%; adjusted OR 2.3, 95% CI 1.01 to 5.2). Increased SCD risk was associated with sodium channel blocking AEMs (cases 1.6%, controls 0.4%; adjusted OR 2.8, 95% CI 1.1 to 7.2), but not with non-sodium channel blocking AEMs. Carbamazepine and gabapentin were associated with increased SCD risk (carbamazepine: cases 1.1%, controls 0.3%; adjusted OR 3.2, 95% CI 1.1 to 9.2; gabapentin: cases 0.3%, controls 0.1%; adjusted OR 5.7, 95% CI 1.2 to 27.9). CONCLUSIONS: Epilepsy and AEM use are both associated with increased SCD risk in the general population. Poor seizure control contributes to increased SCD risk in epilepsy, while sodium channel blockade contributes to SCD susceptibility in AEM users.

Improved survival after out-of-hospital cardiac arrest and use of automated external defibrillators.

BACKGROUND: In recent years, a wider use of automated external defibrillators (AEDs) to treat out-of-hospital cardiac arrest was advocated in The Netherlands. We aimed to establish whether survival with favorable neurologic outcome after out-of-hospital cardiac arrest has significantly increased, and, if so, whether this is attributable to AED use. METHODS AND RESULTS: We performed a population-based cohort study, including patients with out-of-hospital cardiac arrest from cardiac causes between 2006 and 2012, excluding emergency medical service-witnessed arrests. We determined survival status at each stage (to emergency department, to admission, and to discharge) and examined temporal trends using logistic regression analysis with year of resuscitation as an independent variable. By adding each covariable subsequently to the regression model, we investigated their impact on the odds ratio of year of resuscitation. Analyses were performed according to initial rhythm (shockable versus nonshockable) and AED use. Rates of survival with favorable neurologic outcome after out-of-hospital cardiac arrest increased significantly (N=6133, 16.2% to 19.7%; P for trend=0.021), although solely in patients presenting with a shockable initial rhythm (N=2823; 29.1% to 41.4%; P for trend<0.001). In this group, survival increased at each stage but was strongest in the prehospital phase (odds ratio, 1.11 [95% CI, 1.06-1.16]). Rates of AED use almost tripled during the study period (21.4% to 59.3%; P for trend <0.001), thereby decreasing time from emergency call to defibrillation-device connection (median, 9.9 to 8.0 minutes; P<0.001). AED use statistically explained increased survival with favorable neurologic outcome by decreasing the odds ratio of year of resuscitation to a nonsignificant 1.04. CONCLUSIONS: Increased AED use is associated with increased survival in patients with a shockable initial rhythm. We recommend continuous efforts to introduce or extend AED programs.

Atrial fibrillation is an independent risk factor for ventricular fibrillation: a large-scale population-based case-control study.

BACKGROUND: Atrial fibrillation (AF) is associated with sudden cardiac death. We aimed to study whether AF is associated with ventricular fibrillation (VF), the most common cause of sudden cardiac death and whether this association is independent of confounders, ie, concomitant disease, use of antiarrhythmic or QT-prolonging drugs, and acute myocardial infarction. METHODS AND RESULTS: We performed a community-based case-control study. Cases were patients with out-of-hospital cardiac arrest because of ECG-documented VF. Controls were age-/sex-matched non-VF subjects from the community. VF risk in AF patients was studied by means of (conditional) logistic regression, adjusting for all available confounders. We studied 1397 VF cases and 3474 controls. AF occurred in 215 cases (15.4%) and 90 controls (2.6%). AF was associated with a 3-fold increased risk of VF (adjusted odds ratio, 3.1 [2.1-4.5]). VF risk in AF cases was increased to the same extent across all age/sex groups and in AF cases who had no comorbidity (adjusted odds ratio 3.0 [1.6-5.5]) or used no confounding drugs (antiarrhythmics, 2.4 [1.4-4.3]; QT-prolonging drugs, 3.1 [1.8-5.4]). VF risk was similarly increased in AF cases with acute myocardial infarction-related VF (adjusted odds ratio 2.6 [1.4-4.8]), and those with non-acute myocardial infarction-related VF (adjusted odds ratio 4.3 [1.9-10.1]). CONCLUSIONS: AF is independently associated with a 3-fold increased risk of VF. Comorbidity, use of antiarrhythmic or QT-prolonging drugs, or acute myocardial infarction does not fully account for this increased risk.

Exercise-related out-of-hospital cardiac arrest in the general population: incidence and prognosis.

AIMS: Although regular physical activity has beneficial cardiovascular effects, exercise can trigger an acute cardiac event. We aimed to determine the incidence and prognosis of exercise-related out-of-hospital cardiac arrest (OHCA) in the general population. METHODS AND RESULTS: We prospectively collected all OHCAs in persons aged 10-90 years from January 2006 to January 2009 in the Dutch province North Holland. The relation between exercise during or within 1 h before OHCA and outcome was analysed using multivariable logistic regression, adjusted for age, gender, location, bystander witness, bystander cardiopulmonary resuscitation (CPR), automated external defibrillator (AED) use, initial rhythm, and Emergency Medical System response time. Of 2524 OHCAs, 143 (5.7%) were exercise related (7 ≤35 years, 93% men). Exercise-related OHCA incidence was 2.1 per 100 000 person-years overall and 0.3 per 100 000 person-years in those ≤35 years. Survival after exercise-related OHCA was distinctly better than after non-exercise related OHCA (46.2 vs. 17.2%) [unadjusted odds ratio (OR) 4.12; 95%CI 2.92-5.82; P < 0.001], even after adjustment for abovementioned variables (OR 2.63; 95%CI, 1.23-5.54; P = 0.01). In the 69 victims aged ≤35 years, exercise was not associated with better survival: 14.3 vs. 17.7% in non-exercise-related OHCA (OR 0.77; 95%CI 0.08-7.08; P = 0.82). CONCLUSION: Exercise-related OHCA has a low incidence, particularly in the young. Cardiac arrests occurring during or shortly after exercise carry a markedly better prognosis than non-exercise-related arrests in persons >35 years. This study establishes the favourable outcome of exercise-related OHCA and should have direct implications for public health programs to prevent exercise-related sudden death.

Increased risk of sudden cardiac arrest in obstructive pulmonary disease: a case-control study.

BACKGROUND: We aimed to determine whether (1) patients with obstructive pulmonary disease (OPD) have an increased risk of sudden cardiac arrest (SCA) due to ventricular tachycardia or fibrillation (VT/VF), and (2) the SCA risk is mediated by cardiovascular risk-profile and/or respiratory drug use. METHODS: A community-based case-control study was performed, with 1310 cases of SCA of the ARREST study and 5793 age, sex and SCA-date matched non-SCA controls from the PHARMO database. Only incident SCA cases, age older than 40 years, that resulted from unequivocal cardiac causes with electrocardiographic documentation of VT/VF were included. Conditional logistic regression analysis was used to assess the association between SCA and OPD. Pre-specified subgroup analyses were performed regarding age, sex, cardiovascular risk-profile, disease severity, and current use of respiratory drugs. RESULTS: A higher risk of SCA was observed in patients with OPD (n = 190 cases [15%], 622 controls [11%]) than in those without OPD (OR adjusted for cardiovascular risk-profile 1.4 [1.2-1.6]). In OPD patients with a high cardiovascular risk-profile (OR 3.5 [2.7-4.4]) a higher risk of SCA was observed than in those with a low cardiovascular risk-profile (OR 1.3 [0.9-1.9]) The observed SCA risk was highest among OPD patients who received short-acting ß2-adrenoreceptor agonists (SABA) or anticholinergics (AC) at the time of SCA (SABA OR: 3.9 [1.7-8.8], AC OR: 2.7 [1.5-4.8] compared to those without OPD). CONCLUSIONS: OPD is associated with an increased observed risk of SCA. The most increased risk was observed in patients with a high cardiovascular risk-profile, and in those who received SABA and, possibly, those who received AC at the time of SCA.

Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community.

AIMS: Non-cardiac drugs that impair cardiac repolarization (electrocardiographic QT prolongation) are associated with an increased sudden cardiac arrest (SCA) risk. Emerging evidence suggests that non-cardiac drugs that impair cardiac depolarization and excitability (electrocardiographic QRS prolongation) also increase the risk for SCA. Nortriptyline, which blocks the SCN5A-encoded cardiac sodium channel, may exemplify such drugs. We aimed to study whether nortriptyline increases the risk for SCA, and to establish the underlying mechanisms. METHODS AND RESULTS: We studied QRS durations during rest/exercise in an index patient who experienced ventricular tachycardia during exercise while using nortriptyline, and compared them with those of 55 controls with/without nortriptyline and 24 controls with Brugada syndrome (BrS) without nortriptyline, who carried an SCN5A mutation. We performed molecular-genetic (exon-trapping) and functional (patch-clamp) experiments to unravel the mechanisms of QRS prolongation by nortriptyline and the SCN5A mutation found in the index patient. We conducted a prospective community-based study among 944 victims of ECG-documented SCA and 4354-matched controls to determine the risk for SCA associated with nortriptyline use. Multiple mechanisms may act in concert to increase the risk for SCA during nortriptyline use. Pharmacological (nortriptyline), genetic (loss-of-function SCN5A mutation), and/or functional (sodium channel inactivation at fast heart rates) factors conspire to reduce the cardiac sodium current and increase the risk for SCA. Nortriptyline use in the community was associated with a 4.5-fold increase in the risk for SCA [adjusted OR: 4.5 (95% CI: 1.1-19.5)], particularly when other sodium channel-blocking factors were present. CONCLUSIONS: Nortriptyline increases the risk for SCA in the general population, particularly in the presence of genetic and/or non-genetic factors that decrease cardiac excitability by blocking the cardiac sodium channel.

Epilepsy is a risk factor for sudden cardiac arrest in the general population.

BACKGROUND: People with epilepsy are at increased risk for sudden death. The most prevalent cause of sudden death in the general population is sudden cardiac arrest (SCA) due to ventricular fibrillation (VF). SCA may contribute to the increased incidence of sudden death in people with epilepsy. We assessed whether the risk for SCA is increased in epilepsy by determining the risk for SCA among people with active epilepsy in a community-based study. METHODS AND RESULTS: This investigation was part of the Amsterdam Resuscitation Studies (ARREST) in the Netherlands. It was designed to assess SCA risk in the general population. All SCA cases in the study area were identified and matched to controls (by age, sex, and SCA date). A diagnosis of active epilepsy was ascertained in all cases and controls. Relative risk for SCA was estimated by calculating the adjusted odds ratios using conditional logistic regression (adjustment was made for known risk factors for SCA). We identified 1019 cases of SCA with ECG-documented VF, and matched them to 2834 controls. There were 12 people with active epilepsy among cases and 12 among controls. Epilepsy was associated with a three-fold increased risk for SCA (adjusted OR 2.9 [95%CI 1.1-8.0.], p=0.034). The risk for SCA in epilepsy was particularly increased in young and females. CONCLUSION: Epilepsy in the general population seems to be associated with an increased risk for SCA.

A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes.

BACKGROUND: Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. METHODS AND RESULTS: In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects. CONCLUSIONS: This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.

Impact of onsite or dispatched automated external defibrillator use on survival after out-of-hospital cardiac arrest.

BACKGROUND: There have been few studies on the effectiveness of bystander automated external defibrillator (AED) use in out-of-hospital cardiac arrest. The objective of this study was to determine whether actual use of onsite or dispatched AED reduces the time to first shock compared with no AED use and thereby improves survival. METHODS AND RESULTS: We performed a population-based cohort study of 2833 consecutive patients with a nontraumatic out-of-hospital cardiac arrest before emergency medical system arrival between 2006 and 2009. The primary outcome, neurologically intact survival to discharge, was compared by use of multivariable logistic regression analysis. An onsite AED had been applied in 128 of the 2833 cases, a dispatched AED in 478, and no AED in 2227. Onsite AED use reduced the time to first shock from 11 to 4.1 minute. Neurologically intact survival was 49.6% for patients treated with an onsite AED compared with 14.3% without an AED (unadjusted odds ratio, 5.63; 95% confidence interval, 3.91-8.10). The odds ratio remained statistically significant after adjustment for confounding (odds ratio, 2.72; 95% confidence interval, 1.77-4.18). Dispatched AED use reduced the time from call to first shock to 8.5 minutes. Neurologically intact survival was 17.2% for patients treated with a dispatched AED (unadjusted odds ratio, 1.07; 95% confidence interval, 0.82-1.39). Every year, onsite AEDs saved 3.6 lives per 1 million inhabitants; dispatched AEDs saved 1.2 lives. CONCLUSIONS: The use of an onsite AED leads to a doubling of neurologically intact survival. In our system, the survival benefit of dispatched AED use was much smaller than that of onsite AED use.

Differential changes in QTc duration during in-hospital haloperidol use.

AIMS: To evaluate changes in QT duration during low-dose haloperidol use, and determine associations between clinical variables and potentially dangerous QT prolongation. METHODS: In a retrospective cohort study in a tertiary university teaching hospital in The Netherlands, all 1788 patients receiving haloperidol between 2005 and 2007 were studied; ninety-seven were suitable for final analysis. Rate-corrected QT duration (QTc) was measured before, during and after haloperidol use. Clinical variables before haloperidol use and at the time of each ECG recording were retrieved from hospital charts. Mixed model analysis was used to estimate changes in QT duration. Risk factors for potentially dangerous QT prolongation were estimated by logistic regression analysis. RESULTS: Patients with normal before-haloperidol QTc duration (male ≤430 ms, female ≤450 ms) had a significant increase in QTc duration of 23 ms during haloperidol use; twenty-three percent of patients rose to abnormal levels (male ≥450 ms, female ≥470 ms). In contrast, a significant decrease occurred in patients with borderline (male 430-450 ms, female 450-470 ms) or abnormal before-haloperidol QTc duration (15 ms and 46 ms, respectively); twenty-three percent of patients in the borderline group, and only 9% of patients in the abnormal group obtained abnormal levels. Potentially dangerous QTc prolongation was independently associated with surgery before haloperidol use (OR(adj) 34.9, p = 0.009) and before-haloperidol QTc duration (OR(adj) 0.94, p = 0.004). CONCLUSION: QTc duration during haloperidol use changes differentially, increasing in patients with normal before-haloperidol QTc duration, but decreasing in patients with prolonged before-haloperidol QTc duration. Shorter before-haloperidol QTc duration and surgery before haloperidol use predict potentially dangerous QTc prolongation.

Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

The site of origin of torsade de pointes.

OBJECTIVE: The electrocardiographic (ECG) characteristics and mode of onset of torsade de pointes (TdP) are well described. Less is known about the site of onset of this arrhythmia. This study was conducted to determine if arrhythmias in the long QT syndrome (LQTS) have a predominant site of origin. DESIGN: A retrospective analysis of all episodes of LQTS-related arrhythmias recorded in two university hospitals. PATIENTS: Patients with LQTS and no structural heart disease, for whom simultaneous 6-12 leads ECG recording of the onset of TdP was available, were included. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The site of origin of TDP was defined according to the morphology of the initiating ventricular complex based on validated criteria. Multiple-lead recordings of 1025 LQTS-related arrhythmias, including 151 episodes of TdP and 874 QT-related extrasystoles (impending TdP) were available for 50 patients. RESULTS: The site of origin of TdP was not homogeneously distributed (p<0.001). Instead, the majority of episodes of TdP (56%) and most QT-related extrasystoles (70%) originated from the outflow tract. There was no correlation between site of origin and the aetiology of LQTS or the QT duration. On a given patient, multiple episodes of TdP tended to originate from the same area and the site of origin of QT-related extrasystoles correlated with the site of origin of TdP. CONCLUSION: The most frequent site of origin of TdP is the outflow tract. Further studies are needed to understand why this relatively small area of the ventricle is a predominant site of origin of diverse ventricular arrhythmias.

Incidence, causes, and outcomes of out-of-hospital cardiac arrest in children. A comprehensive, prospective, population-based study in the Netherlands.

OBJECTIVES: This study sought to determine comprehensively the incidence of pediatric out-of-hospital cardiac arrest (OHCA) and its contribution to total pediatric mortality, the causes of pediatric OHCA, and the outcome of resuscitation of pediatric OHCA patients. BACKGROUND: There is a paucity of complete studies on incidence, causes, and outcomes of pediatric OHCA. METHODS: In this prospective, population-based study, OHCA victims younger than age 21 years in 1 province of the Netherlands were registered through both emergency medical services and coroners over a period of 4.3 years. Death certificate data on total pediatric mortality, survival status, and neurological outcome at hospital discharge also were obtained. RESULTS: With a total mortality of 923 during the study period and 233 victims of OHCA (including 221 who died and 12 who survived), OHCA caused 24% (221 of 923) of total pediatric mortality. Natural causes of OHCA amounted to 115 (49%) cases, with cardiac causes being most prevalent (n = 90, 39%). The incidence of pediatric OHCA was 9.0 per 100,000 pediatric person-years (95% confidence interval: 7.8 to 10.3), whereas the incidence of pediatric OHCA from cardiac causes was 3.2 (95% confidence interval: 2.5 to 3.9). Of 51 resuscitated patients, 12 (24%) survived; among survivors, 10 (83%) had a neurologically intact outcome. CONCLUSIONS: Out-of-hospital cardiac arrest accounts for a significant proportion of pediatric mortality, and cardiac causes are the most prevalent causes of OHCA. The vast majority of OHCA survivors have a neurologically intact outcome.

A complex double deletion in LMNA underlies progressive cardiac conduction disease, atrial arrhythmias, and sudden death.

BACKGROUND: Cardiac conduction disease is a clinically and genetically heterogeneous disorder characterized by defects in electrical impulse generation and conduction and is associated with sudden cardiac death. METHODS AND RESULTS: We studied a 4-generation family with autosomal dominant progressive cardiac conduction disease, including atrioventricular conduction block and sinus bradycardia, atrial arrhythmias, and sudden death. Genome-wide linkage analysis mapped the disease locus to chromosome 1p22-q21. Multiplex ligation-dependent probe amplification analysis of the LMNA gene, which encodes the nuclear-envelope protein lamin A/C, revealed a novel gene rearrangement involving a 24-bp inversion flanked by a 3.8-kb deletion upstream and a 7.8-kb deletion downstream. The presence of short inverted sequence homologies at the breakpoint junctions suggested a mutational event involving serial replication slippage in trans during DNA replication. CONCLUSIONS: We identified for the first time a complex LMNA gene rearrangement involving a double deletion in a 4-generation Dutch family with progressive conduction system disease. Our findings underscore the fact that if conventional polymerase chain reaction-based direct sequencing approaches for LMNA analysis are negative in suggestive pedigrees, mutation detection techniques capable of detecting gross genomic lesions involving deletions and insertions should be considered.

Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction.

Sudden cardiac death from ventricular fibrillation during acute myocardial infarction is a leading cause of total and cardiovascular mortality. To our knowledge, we here report the first genome-wide association study for this trait, conducted in a set of 972 individuals with a first acute myocardial infarction, 515 of whom had ventricular fibrillation and 457 of whom did not, from the Arrhythmia Genetics in The Netherlands (AGNES) study. The most significant association to ventricular fibrillation was found at 21q21 (rs2824292, odds ratio = 1.78, 95% CI 1.47-2.13, P = 3.3 x 10(-10)). The association of rs2824292 with ventricular fibrillation was replicated in an independent case-control set consisting of 146 out-of-hospital cardiac arrest individuals with myocardial infarction complicated by ventricular fibrillation and 391 individuals who survived a myocardial infarction (controls) (odds ratio = 1.49, 95% CI 1.14-1.95, P = 0.004). The closest gene to this SNP is CXADR, which encodes a viral receptor previously implicated in myocarditis and dilated cardiomyopathy and which has recently been identified as a modulator of cardiac conduction. This locus has not previously been implicated in arrhythmia susceptibility.

Giant T-U waves precede torsades de pointes in long QT syndrome: a systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation.

OBJECTIVES: This study sought to identify electrocardiographic (ECG) criteria that are associated with initiation of torsades de pointes (TdP) in patients with acquired (a-) and congenital (c-) long QT syndrome (LQTS). BACKGROUND: Electrocardiographic criteria used as risk predictors for TdP commonly rely on a prolonged QT interval but rarely consider abnormal T-U waves. METHODS: We analyzed ECG recordings with TdP from 35 LQTS patients (15 c-LQTS and 20 a-LQTS) and compared them with premature ventricular complexes (PVCs) from 40 patients with normal QT intervals and with PVCs in 24 of the 35 LQTS patients not related to TdP. RESULTS: Abnormal T-U waves (6.2 +/- 0.9 mm) directly preceded TdP in 34 of 35 LQTS patients and were larger than T-wave amplitude (2.8 +/- 0.2 mm) in control patients and larger than the largest T-U-wave in LQTS without TdP (4.7 +/- 0.8 mm). The TdP-initiating beat emerged from a T-U-wave in 27 of 35 LQTS patients and in none of 40 control patients. The QRS duration of the first TdP beat (175 +/- 12 ms) was longer than in control PVCs (145 +/- 4 ms) and in PVCs in LQTS patients not related to TdP (138 +/- 22 ms). The QRS angle was less steep before TdP than in other PVCs (all p < 0.05). CONCLUSIONS: Abnormal, giant T-U waves separate TdP initiation in LQTS patients from PVCs in other heart disease and from other PVCs in LQTS patients. These ECG analyses suggest that early afterdepolarizations initiate TdP and, if present, may help to identify an imminent risk for TdP.