Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation.

Aims: A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts.

Methods And Results: The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies.

Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy.

Genetic variants in CYP2C9 and VKORC1 strongly affect steady-state warfarin dose. However, these variants also affect early international normalized ratio (INR) values during warfarin initiation. We examined whether CYP2C9/VKORC1 genotypes provide information about warfarin sensitivity additional to that provided by early INR responses.

Rate-independent QT shortening during exercise in healthy subjects: terminal repolarization does not shorten with exercise.

Introduction: QT interval for a given heart rate differs between exercise and recovery (QT hysteresis) due to slow QT adaptation to changes in heart rate. We hypothesized that QT hysteresis is evident within stages of exercise and investigated which component of the QT contributes to hysteresis.

Methods And Results: Nineteen healthy volunteers performed a staged exercise test (four stages, 3 min each).

A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose.

Warfarin dosing is correlated with polymorphisms in vitamin K epoxide reductase complex 1 (VKORC1) and the cytochrome P450 2C9 (CYP2C9) genes. Recently, the FDA revised warfarin labeling to raise physician awareness about these genetic effects. Randomized clinical trials are underway to test genetically based dosing algorithms.

Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans.

Brugada syndrome is a genetic disease associated with sudden cardiac death that is characterized by ventricular fibrillation and right precordial ST segment elevation on ECG. Loss-of-function mutations in SCN5A, which encodes the predominant cardiac sodium channel alpha subunit NaV1.5, can cause Brugada syndrome and cardiac conduction disease.

The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.

Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A.

Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.

Background: Genetic studies have identified ion channel gene variants in families segregating atrial fibrillation (AF), the most common arrhythmia in clinical practice. Here, we tested the hypothesis that vulnerability to AF is associated with variation in SCN5A, the gene encoding the cardiac sodium channel.

Methods And Results: We resequenced the entire SCN5A coding region in 375 subjects with either lone AF (n=118) or AF associated with heart disease (n=257).

Prolonged signal-averaged P-wave duration as an intermediate phenotype for familial atrial fibrillation.

Objectives: This study sought to perform a genome-wide linkage analysis in a large atrial fibrillation (AF) kindred using AF and abnormally prolonged signal-averaged (SA) P-wave duration as the phenotype.

Background: Although inherited forms of AF exist, phenotypic complexity has limited efforts to ascertain mutation carriers and thus identify causal genes. The identification of intermediate or endophenotypes may accelerate this effort.

Genetic determinants of response to warfarin during initial anticoagulation.

Background: Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9), and of a key pharmacologic target of warfarin, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to various warfarin doses, but the role of these variants during initial anticoagulation is not clear.

Methods: In 297 patients starting warfarin therapy, we assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the international normalized ratio [INR]), and bleeding events. The study outcomes were the time to the first INR within the therapeutic range, the time to the first INR of more than 4, the time above the therapeutic INR range, the INR response over time, and the warfarin dose requirement.

Persistent atrial fibrillation is associated with reduced risk of torsades de pointes in patients with drug-induced long QT syndrome.

Objectives: The goal of this study was to identify markers of torsades de pointes (TdP) in patients with drug-associated long QT syndrome (LQTS).

Background: Drug-induced LQTS includes individuals developing marked prolongation of ventricular repolarization on exposure to an offending drug. Under these conditions, TdP develops in some but not all patients.

A genetic framework for improving arrhythmia therapy.

Abnormalities in heart rhythm continue to cause high rates of illness and death. Better treatment could be provided by solving two main challenges: the early identification of patients who are at risk, and the characterization of molecular pathways that culminate in arrhythmias. By analysing mechanisms that increase susceptibility to arrhythmia in individuals with genetic syndromes, it might be possible to improve current therapies and to develop new ways to treat and prevent common arrhythmias.

Metabolic syndrome and risk of development of atrial fibrillation: the Niigata preventive medicine study.

Background: The metabolic syndrome consists of a cluster of atherosclerotic risk factors, many of which also have been implicated in the genesis of atrial fibrillation (AF). However, the precise role of the metabolic syndrome in the development of AF is unknown.

Methods And Results: This prospective, community-based, observational cohort study was based on an annual health check-up program in Japan.

Cardiac potassium channel dysfunction in sudden infant death syndrome.

Life-threatening arrhythmias have been suspected as one cause of the sudden infant death syndrome (SIDS), and this hypothesis is supported by the observation that mutations in arrhythmia susceptibility genes occur in 5-10% of cases. However, the functional consequences of cardiac potassium channel gene mutations associated with SIDS and how these alleles might mechanistically predispose to sudden death are unknown. To address these questions, we studied four missense KCNH2 (encoding HERG) variants, one compound KCNH2 genotype, and a missense KCNQ1 mutation all previously identified in Norwegian SIDS cases.

Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges.

Serious adverse drug reactions (SADRs) are a major cause of morbidity and mortality worldwide. Some SADRs may be predictable, based upon a drug's pharmacodynamic and pharmacokinetic properties. Many, however, appear to be idiosyncratic.

A memorable experience.

The electrocardiographic phenomenon of cardiac memory results from aberrant ventricular activation and causes transient ECG features that can mimic ischaemia. We present the case of a patient with ischaemic cardiomyopathy who exhibited evidence of T-wave memory in the setting of multiple episodes of non-sustained ventricular tachycardia that were triggered by an insect bite.

Plasminogen activator inhibitor-1 as a predictor of postoperative atrial fibrillation after cardiopulmonary bypass.

Background: Postoperative atrial fibrillation (AF), leading to significant morbidity and prolongation of hospital stay, complicates 20% to 40% of surgical procedures requiring cardiopulmonary bypass (CPB). This study tests the hypothesis that biomarkers predict the development of postoperative AF.

Methods And Results: We enrolled 253 adult patients undergoing elective cardiac surgery requiring CPB and who were in sinus rhythm at the time of surgery.

Autonomic tone attenuates drug-induced QT prolongation.

Introduction: The QT interval is a predictor of sudden death. Many drugs prolong the QT, primarily through I(Kr) block. Autonomic tone directly affects heart rate and ventricular repolarization, but its effects in the setting of I(Kr) block are unknown.

Molecular cloning and analysis of zebrafish voltage-gated sodium channel beta subunit genes: implications for the evolution of electrical signaling in vertebrates.

Background: Action potential generation in excitable cells such as myocytes and neurons critically depends on voltage-gated sodium channels. In mammals, sodium channels exist as macromolecular complexes that include a pore-forming alpha subunit and 1 or more modulatory beta subunits. Although alpha subunit genes have been cloned from diverse metazoans including flies, jellyfish, and humans, beta subunits have not previously been identified in any non-mammalian species.

Polymorphism modulates symptomatic response to antiarrhythmic drug therapy in patients with lone atrial fibrillation.

Background: The angiotensin-converting enzyme (ACE) deletion allele, ACE D, is associated with increased ACE activity and adverse outcomes in cardiovascular disease. Although activation of the renin-angiotensin-aldosterone system (RAAS) now appears to play a role in the pathophysiology of atrial fibrillation (AF), it remains to be determined if ACE genotype impacts response to conventional AAD therapy in patients with AF.

Objectives: The purpose of this study was to investigate whether response to antiarrhythmic drug (AAD) therapy in patients with AF is modulated by the ACE I/D polymorphism.