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.

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).

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.

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).

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.

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.

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).

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

Rapid assay to detect possible natural substrates of proteases in living cells.

Proteolysis is a regulatory step in many physiological processes, but which proteases in what cellular sites are involved in activation or degradation of which peptides is not well known. We developed a rapid assay consisting of living cells and fluorogenic protease substrates to determine which bioactive peptides are possible natural substrates of a specific protease with the multifunctional or moonlighting protein CD26/dipeptidyl peptidase IV (DPPIV) as a model. CD26/DPPIV catalyzes cleavage of peptides from the amino terminus of peptides with proline at the penultimate position.

Fluorogenic substrate [Ala-Pro]2-cresyl violet but not Ala-Pro-rhodamine 110 is cleaved specifically by DPPIV activity: a study in living Jurkat cells and CD26/DPPIV-transfected Jurkat cells.

Fluorogenic substrates [Ala-Pro](2)-cresyl violet and Ala-Pro-rhodamine 110 have been tested for microscopic detection of protease activity of dipeptidyl peptidase IV (DPPIV) in living cells. DPPIV activity is one of the many functions of the multifunctional or moonlighting protein CD26/DPPIV. As a model we used Jurkat cells, which are T-cells that lack CD26/DPPIV expression, and CD26/DPPIV-transfected Jurkat cells.