Marieke T. Blom

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.

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.

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).

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.

Implantable Cardioverter-Defibrillators Have Reduced the Incidence of Resuscitation for Out-of-Hospital Cardiac Arrest Caused by Lethal Arrhythmias

Background— Over the last decades, a gradual decrease in ventricular fibrillation (VF) as initial recorded rhythm during resuscitation for out-of-hospital cardiac arrest (OHCA) has been noted. We sought to establish the contribution of implantable cardioverter-defibrillator (ICD) therapy to this decline. Methods and Results— Using a prospective database of all OHCA resuscitation in the province North Holland in the Netherlands (Amsterdam Resuscitation Studies [ARREST]), we collected data on all patients in whom resuscitation for OHCA was attempted in 2005–2008. VF OHCA incidence (per 100 000 inhabitants per year) was compared with VF OHCA incidence data during 1995–1997, collected in a similar way. We also collected ICD interrogations of all ICD patients from North Holland and identified all appropriate ICD shocks in 2005–2008; we calculated the number of prevented VF OHCA episodes, considering that only part of the appropriate shocks would result in avoided resuscitation. VF OHCA incidence decreased from 21.1/100 000 in 1995–1997 to 17.4/100 000 in 2005–2008 (P<0.001). Non-VF OHCA increased from 12.2/100 000 to 19.4/100 000 (P<0.001). VF as presenting rhythm declined from 63% to 47%. In 2005–2008, 1972 ICD patients received 977 shocks. Of these shocks, 339 were caused by a life-threatening arrhythmia. We estimate that these 339 shocks have prevented 81 (minimum, 39; maximum, 152) cases of VF OHCA, corresponding with 33% (minimum, 16%; maximum, 63%) of the observed decline in VF OHCA incidence. Conclusions— The incidence of VF OHCA decreased over the last 10 years in North Holland. ICD therapy explained a decrease of 1.2/100 000 inhabitants per year, corresponding with 33% of the observed decline in VF OHCA.

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.

SCN5A Mutations in Brugada Syndrome Are Associated with Increased Cardiac Dimensions and Reduced Contractility

Background The cardiac sodium channel (Nav1.5) controls cardiac excitability. Accordingly, SCN5A mutations that result in loss-of-function of Nav1.5 are associated with various inherited arrhythmia syndromes that revolve around reduced cardiac excitability, most notably Brugada syndrome (BrS). Experimental studies have indicated that Nav1.5 interacts with the cytoskeleton and may also be involved in maintaining structural integrity of the heart. We aimed to determine whether clinical evidence may be obtained that Nav1.5 is involved in maintaining cardiac structural integrity. Methods Using cardiac magnetic resonance (CMR) imaging, we compared right ventricular (RV) and left ventricular (LV) dimensions and ejection fractions between 40 BrS patients with SCN5A mutations (SCN5a-mut-positive) and 98 BrS patients without SCN5A mutations (SCN5a-mut-negative). We also studied 18 age/sex-matched healthy volunteers. Results SCN5a-mut-positive patients had significantly larger end-diastolic and end-systolic RV and LV volumes, and lower LV ejection fractions, than SCN5a-mut-negative patients or volunteers. Conclusions Loss-of-function SCN5A mutations are associated with dilatation and impairment in contractile function of both ventricles that can be detected by CMR analysis.

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.