Characterization and mechanisms of action of novel NaV1.5 channel mutations associated with Brugada syndrome.

Background: Brugada syndrome is a heterogeneous heart rhythm disorder characterized by an atypical right bundle block pattern with ST-segment elevation and T-wave inversion in the right precordial leads. Loss-of-function mutations in SCN5A encoding the cardiac sodium channel Na(V)1.5 are associated with Brugada syndrome.

High prevalence of genetic variants previously associated with Brugada syndrome in new exome data.

More than 300 variants in 12 genes have been associated with Brugada syndrome (BrS) which has a prevalence ranging between 1:2000 and 1:100,000. Until recently, there has been little knowledge regarding the distribution of genetic variations in the general population. This problem was partly solved, when exome data from the NHLI GO Exome Sequencing Project (ESP) was published.

A novel KCND3 gain-of-function mutation associated with early-onset of persistent lone atrial fibrillation.

Aims: Atrial fibrillation (AF) is the most common cardiac arrhythmia, and early-onset lone AF has been linked to mutations in genes encoding ion channels. Mutations in the pore forming subunit KV4.3 leading to an increase in the transient outward potassium current (Ito) have previously been associated with the Brugada Syndrome.

Myocardial impulse propagation is impaired in right ventricular tissue of Zucker diabetic fatty (ZDF) rats.

Background: Diabetes increases the risk of cardiovascular complications including arrhythmias, but the underlying mechanisms remain to be established. Decreased conduction velocity (CV), which is an independent risk factor for re-entry arrhythmias, is present in models with streptozotocin (STZ) induced type 1 diabetes. Whether CV is also disturbed in models of type 2 diabetes is currently unknown.

New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.

Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated with these cardiomyopathies, but the disease-causing effect of reported variants is often dubious.

Genetic variation in KCNA5: impact on the atrial-specific potassium current IKur in patients with lone atrial fibrillation.

Aims: Genetic factors may be important in the development of atrial fibrillation (AF) in the young. KCNA5 encodes the potassium channel α-subunit KV1.5, which underlies the voltage-gated atrial-specific potassium current IKur.

Familial atrial fibrillation predicts increased risk of mortality: a study in Danish twins.

Background: Atrial fibrillation (AF) is a common arrhythmia. Several studies have shown association of genetic variants with AF and that familial AF increases the risk of AF. We have previously shown a substantial heritability of AF in a twin study.

AMPK: A regulator of ion channels.

Ion transport processes are highly energy consuming. It is therefore critical to couple ion transport processes to the metabolic state of the cell. An important player in this coupling appears to be the AMP-activated protein kinase (AMPK).

Rare variants in GJA5 are associated with early-onset lone atrial fibrillation.

Background: Genetic factors are believed to be important in early-onset lone atrial fibrillation (AF). The gene GJA5 encodes the gap-junction protein Cx40, which together with Cx43 is responsible for the electrical coupling of the atrial cardiomyocytes. The regulatory single nucleotide polymorphism rs10465885 in GJA5 was recently associated with early-onset lone AF (< 60 years) and was also found to be strongly associated with Cx40 messenger RNA levels.

Mutation analysis of the candidate genes -, , and in patients with arrhythmogenic right ventricular cardiomyopathy.

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart disease characterized by fibrofatty infiltrations in the myocardium, right and/or left ventricular involvement, and ventricular tachyarrhythmias. Although ten genes have been associated with ARVC, only about 40% of the patients have an identifiable disease-causing mutation. In the present study we aimed at investigating the involvement of the genes -, , and in the pathogenesis of ARVC.

The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases.

Introduction: Sudden unexplained death account for one-third of all sudden natural deaths in the young (1-35 years). Hitherto, the prevalence of genopositive cases has primarily been based on deceased persons referred for postmortem genetic testing. These deaths potentially may represent the worst of cases, thus possibly overestimating the prevalence of potentially disease causing mutations in the 3 major long-QT syndrome (LQTS) genes in the general population.

Prior myocardial infarction in the young: predisposes to a high relative risk but low absolute risk of a sudden cardiac death.

Aims: The study reports the relative and absolute risk of sudden cardiac death (SCD) in patients <36 years with prior myocardial infarction (MI).

Methods And Results: Through review of death certificates, we identified all SCDs in Danes aged 18-35 years between 1 January 2000 until 31st December 2006. We then used the unique Danish civil registration number, which enabled us to follow all Danes in national registries, in the same period.

High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia. The cardiac sodium channel, Na(V)1.5, plays a pivotal role in setting the conduction velocity and the initial depolarization of the cardiac myocytes.

Impact of KChIP2 on Cardiac Electrophysiology and the Progression of Heart Failure.

Electrophysiological remodeling of cardiac potassium ion channels is important in the progression of heart failure. A reduction of the transient outward potassium current (I(to)) in mammalian heart failure is consistent with a reduced expression of potassium channel interacting protein 2 (KChIP2, a K(V)4 subunit). Approaches have been made to investigate the role of KChIP2 in shaping cardiac I(to), including the use of transgenic KChIP2 deficient mice and viral overexpression of KChIP2.

Specificity of elevated intercostal space ECG recording for the type 1 Brugada ECG pattern.

Background: Right precordial (V1-3) elevated electrode placement ECG (EEP-ECG) is often used in the diagnosis of Brugada syndrome (BrS). However, the specificity of this has only been studied in smaller studies in Asian populations. We aimed to study this in a larger European population.

Mutations in the potassium channel subunit KCNE1 are associated with early-onset familial atrial fibrillation.

Background: Atrial fibrillation (AF) is the most common arrhythmia. The potassium current IKs is essential for cardiac repolarization. Gain-of-function mutations in KV7.

Effects of ventricular pacing protocol on electrical restitution assessments in guinea-pig heart.

The steep slope of the rate adaptation of ventricular action potential duration (APD) is thought to indicate profibrillatory tendency. In cardiac patients, APD restitution is commonly assessed by extrasystolic (S(1)-S(2)) stimulations rather than dynamic pacing, because the latter may provoke myocardial ischaemia. In this study, ventricular APD and effective refractory period (ERP) were measured in perfused guinea-pig hearts to determine whether S(1)-S(2) stimulations and dynamic pacing may have similar value in APD restitution assessments aimed to predict arrhythmic risk.

High prevalence of genetic variants previously associated with LQT syndrome in new exome data.

To date, hundreds of variants in 13 genes have been associated with long QT syndrome (LQTS). The prevalence of LQTS is estimated to be between 1:2000 and 1:5000. The knowledge of genetic variation in the general population has until recently been limited, but newly published data from NHLBI GO Exome Sequencing Project (ESP) has provided important knowledge on this topic.

Electrophysiological determinants of arrhythmic susceptibility upon endocardial and epicardial pacing in guinea-pig heart.

Aim: Endocardial pacing instituted to treat symptomatic bradycardia may nevertheless promote tachyarrhythmia in some pacemaker-implanted patients. We sought to determine the contributing electrophysiological mechanisms.

Methods: Left ventricular (LV) monophasic action potential duration (APD(90)) and effective refractory periods were determined in perfused guinea-pig hearts along with volume-conducted ECG recordings during epicardial and endocardial stimulations.

Genetic loci on chromosomes 4q25, 7p31, and 12p12 are associated with onset of lone atrial fibrillation before the age of 40 years.

Background: Three distinct genetic loci on chromosomes 1q21, 4q25, and 16q22 have been associated with atrial fibrillation (AF) in genome-wide association studies (GWAS). Five additional loci have been associated primarily with the PR interval and subsequently with AF. We aimed to investigate if 8 single nucleotide polymorphisms (SNPs), representing the 8 genomic loci previously linked with AF in genome-wide association studies, were associated with early-onset lone AF.

Low disease prevalence and inappropriate implantable cardioverter defibrillator shock rate in Brugada syndrome: a nationwide study.

Aims: Brugada syndrome (BrS) is an inherited channelopathy that predisposes to malignant ventricular arrhythmias and thereby syncope and sudden cardiac death. Prior studies characterizing BrS patients have used highly selected referral populations from tertiary centres and prevalence estimates have been carried out using electrocardiogram (ECG) surveys only. We aimed to identify and characterize all diagnosed BrS patients in Denmark (population 5.

Sodium current and potassium transient outward current genes in Brugada syndrome: screening and bioinformatics.

Background: Brugada syndrome (BrS) is a primary arrhythmia syndrome characterized by the occurrence of malignant ventricular arrhythmias. Previously, the genes SCN1B, SCN3B, MOG1, and KCND3 have been associated with BrS. Recent data from exome screening efforts permit better discrimination between low-frequency genetic variants and true monogenetic disease-causing variants.

SCN1Bb R214Q found in 3 patients: 1 with Brugada syndrome and 2 with lone atrial fibrillation.

Background: SCN1Bb encodes the β-subunit of the sodium channel. A mutation in SCN1Bb R214Q has recently been shown both to increase the Kv4.3 current and to decrease the sodium current.

Deubiquitylating enzyme USP2 counteracts Nedd4-2-mediated downregulation of KCNQ1 potassium channels.

Background: KCNQ1 (Kv7.1), together with its KCNE β subunits, plays a pivotal role both in the repolarization of cardiac tissue and in water and salt transport across epithelial membranes. Nedd4/Nedd4-like (neuronal precursor cell-expressed developmentally downregulated 4) ubiquitin-protein ligases interact with the KCNQ1 potassium channel through a PY motif located in the C terminus of KCNQ1.