Abdennasser Bardai

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 × 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.

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.

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.

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.

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.

Fever Increases the Risk for Cardiac Arrest in the Brugada Syndrome

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Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications.

Background— The identification of the molecular-genetic substrate underlying the various forms of the congenital long-QT syndrome (LQTS) has sparked studies into possible genotype–phenotype correlations with the aim of developing genotype-tailored therapy. The onset of torsade de pointes (TdP) may differ among LQTS patients, being pause dependent in some but not all. This disparity may point to different arrhythmia mechanisms and may affect therapy strategies. We studied whether the proportion of pause-dependent TdP onset varies among LQTS genotypes. Methods and Results— We studied all LQT1 (n=10), LQT2 (n=34), and LQT3 (n=6) patients from 4 centers for whom ECGs of TdP onset were available and analyzed whether pauses preceded TdP onset (first available ECG per patient). Pauses preceded TdP significantly more often in LQT2 (68%) than in LQT1 (0%), and the interval immediately before TdP (pause interval) was significantly longer in LQT2 than in LQT1. The proportion of pause dependence in LQT3 (33%) appeared intermediate, but this group was too small for statistical analysis. Conclusions— Pause dependence of TdP onset is predominant in LQT2 but absent or rare in LQT1. It is suggested that disparities in pause dependence of TdP onset may reflect different arrhythmia mechanisms.

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).

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.

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.