Multisite Validation of a Functional Assay to Adjudicate Brugada Syndrome-Associated Variants.

Background: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in . Interpreting the pathogenicity of missense variants is challenging, and ≈79% of missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification.

Multi-site validation of a functional assay to adjudicate Brugada Syndrome-associated variants.

Brugada Syndrome (BrS) is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in the cardiac sodium channel gene, . Interpreting the pathogenicity of missense variants is challenging and ~79% of missense variants in ClinVar are currently classified as Variants of Uncertain Significance (VUS). An -BrS automated patch clamp assay was generated for high-throughput functional studies of Na1.

Epsilon wave uncovered by exercise test in a patient with desmoplakin-positive arrhythmogenic right ventricular cardiomyopathy.

Epsilon waves are a major criterion for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) but are an insensitive sign. Recently, exercise testing has been shown to uncover epsilon waves in asymptomatic patients carrying mutations in the PKP2 gene. We describe a case of an asymptomatic carrier of a mutation in the DSP gene who had a normal baseline electrocardiogram and an exercise-induced epsilon wave.

Evaluation of genes encoding for the transient outward current (Ito) identifies the KCND2 gene as a cause of J-wave syndrome associated with sudden cardiac death.

Background: J-wave ECG patterns are associated with an increased risk of sudden arrhythmic death, and experimental evidence supports a transient outward current (I(to))-mediated mechanism of J-wave formation. This study aimed to determine the frequency of genetic mutations in genes encoding the I(to) in patients with J waves on ECG.

Methods And Results: Comprehensive mutational analysis was performed on I(to)-encoding KCNA4, KCND2, and KCND3 genes, as well as the previously described J-wave-associated KCNJ8 gene, in 51 unrelated patients with ECG evidence defining a J-wave syndrome.

Kinetics of drug interaction with the Kv11.1 potassium channel.

The Kv11.1 potassium channel is the molecular target for the majority of drugs implicated in acquired long QT syndrome, the most common cause of drug-induced sudden cardiac death, and a common reason for drug restriction or withdrawal from the market. While the IC50 for block of Kv11.

Exercise testing in asymptomatic gene carriers exposes a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy.

Objectives: The aim of this study was to determine if exercise testing could expose a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy (ARVC) in asymptomatic gene carriers.

Background: Management of asymptomatic ARVC gene carriers is challenging because of variable penetrance of disease and the recognition that sudden cardiac death may be the first clinical manifestation.

Methods: Exercise-induced abnormalities during exercise treadmill testing (ETT) were initially compared in 60 subjects: 30 asymptomatic ARVC gene carriers and 30 healthy controls.

Genetics of cardiac electrical disease.

Few tragedies compare to the sudden death of a family member. Sadly, this may represent the first sign of a familial vulnerability to such events. One common cause is an inherited cardiac arrhythmia syndrome.

hERG K(+) channels: structure, function, and clinical significance.

The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel, Kv11.1, which are expressed in the heart, various brain regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines. However, it is the role that Kv11.

Anticoagulation bridging around device surgery: compliance with guidelines.

Background: Current guidelines recommend bridging anticoagulation in patients undergoing cardiac rhythm device surgery with a "moderate to high risk" of thromboembolism. Patients at "low risk" are advised to stop oral anticoagulation without bridging to the procedure. This study examines real world adherence to accepted guidelines and the clinical sequelae of nonadherence.

The genetics of cardiac disease associated with sudden cardiac death: a paper from the 2011 William Beaumont Hospital Symposium on molecular pathology.

Sudden cardiac death due to ventricular arrhythmia most commonly occurs in the setting of coronary artery disease. However, a number of inherited syndromes have now been identified that carry a significant risk of sudden cardiac death and that are disproportionately represented in the young. Arrhythmia in such conditions may result from genetically mediated structural heart disease (eg, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy) or from altered function of cardiac ion channels in the absence of overt structural disease (eg, Brugada syndrome and long QT syndrome).

Degenerating regenerating torsades de pointes.

Ventricular fibrillation (VF) commonly ends in death. Isolated case reports describe the uncommon occurrence of spontaneous termination of VF. Torsades de pointes (TdP), a peculiar form of polymorphic ventricular tachycardia associated with a prolonged QT interval on the surface electrocardiogram, most often spontaneously terminates and then returns to the underlying rhythm.

Greater response to cardiac resynchronization therapy in patients with true complete left bundle branch block: a PREDICT substudy.

Aims: Cardiac resynchronization therapy (CRT) benefits patients with heart failure and a wide QRS complex. Still, one-third derive no clinical benefit and a majority of patients demonstrate no objective improvement of left ventricular (LV) function. Left bundle branch block (LBBB) is a strong predictor of response to CRT.

The role of atrial natriuretic peptide in modulating cardiac electrophysiology.

Since the discovery of atrial natriuretic peptide (ANP) in 1981, significant progress has been made in understanding the mechanism of its release and its role in salt and water balance in the body. It has also become clear that ANP plays a key role in cardiac electrophysiology, modulating the autonomic nervous system and regulating the function of cardiac ion channels. The clinical importance of this role was established when mutations in NPPA, the gene encoding ANP, were identified as a cause of familial atrial fibrillation.

Human ether-a-go-go related gene (hERG) K+ channels: function and dysfunction.

The human Ether-a-go-go Related Gene (hERG) potassium channel plays a central role in regulating cardiac excitability and maintenance of normal cardiac rhythm. Mutations in hERG cause a third of all cases of congenital long QT syndrome, a disorder of cardiac repolarisation characterised by prolongation of the QT interval on the surface electrocardiogram, abnormal T waves, and a risk of sudden cardiac death due to ventricular arrhythmias. Additionally, the hERG channel protein is the molecular target for almost all drugs that cause the acquired form of long QT syndrome.

Drug binding to the inactivated state is necessary but not sufficient for high-affinity binding to human ether-à-go-go-related gene channels.

Drug block of the human ether-à-go-go-related gene K(+) channel (hERG) is the most common cause of acquired long QT syndrome, a disorder of cardiac repolarization that may result in ventricular tachycardia and sudden cardiac death. We investigated the open versus inactivated state dependence of drug block by using hERG mutants N588K and N588E, which shift the voltage dependence of inactivation compared with wild-type but in which the mutated residue is remote from the drug-binding pocket in the channel pore. Four high-affinity drugs (cisapride, dofetilide, terfenadine, and astemizole) demonstrated lower affinity for the inactivation-deficient N588K mutant hERG channel compared with N588E and wild-type hERG.