MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish.

Altered phosphodiesterase (PDE)-cyclic AMP (cAMP) activity is frequently associated with anxiety disorders, but current therapies act by reducing neuronal excitability rather than targeting PDE-cAMP-mediated signaling pathways. Here, we report the novel repositioning of anti-cancer MEK inhibitors as anxiolytics in a zebrafish model of anxiety-like behaviors. PDE inhibitors or activators of adenylate cyclase cause behaviors consistent with anxiety in larvae and adult zebrafish.

High interobserver variability in the assessment of epsilon waves: Implications for diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Background: Revision of the Task Force diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) has increased their sensitivity for the diagnosis of early and familial forms of the disease. The epsilon wave is a major diagnostic criterion in the context of ARVC/D, which, however, remains not quantifiable and therefore may leave room for substantial subjective interpretation.

Objective: The purpose of this study was to assess interobserver agreement in epsilon wave definition and epsilon wave importance for ARVC/D diagnosis.

Diagnostic accuracy of pace spikes in the electrocardiogram to diagnose paced rhythm.

Objective: To determine how often cardiac resynchronization therapy (CRT) pacing systems generate visible pace spikes in the electrocardiogram (ECG).

Methods: In 46 patients treated with CRT pacing systems, we recorded ECGs during intrinsic rhythm, atrial pacing and ventricular pacing. ECGs were analysed for atrial and ventricular pace spikes by two experienced ECG readers blinded to the pacing therapy and to the study purpose.

Auxiliary KCNE subunits modulate both homotetrameric Kv2.1 and heterotetrameric Kv2.1/Kv6.4 channels.

The diversity of the voltage-gated K(+) (Kv) channel subfamily Kv2 is increased by interactions with auxiliary β-subunits and by assembly with members of the modulatory so-called silent Kv subfamilies (Kv5-Kv6 and Kv8-Kv9). However, it has not yet been investigated whether these two types of modulating subunits can associate within and modify a single channel complex simultaneously. Here, we demonstrate that the transmembrane β-subunit KCNE5 modifies the Kv2.

Diet-induced pre-diabetes slows cardiac conductance and promotes arrhythmogenesis.

Background: Type 2 diabetes is associated with abnormal electrical conduction and sudden cardiac death, but the pathogenic mechanism remains unknown. This study describes electrophysiological alterations in a diet-induced pre-diabetic rat model and examines the underlying mechanism.

Methods: Sprague-Dawley rats were fed either high-fat diet and fructose water or normal chow and water for 6 weeks.

Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval.

Aims: We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have an effect on the QTc interval in a Danish population sample. Furthermore, we assessed whether carriers of variants in cLQTS-associated genes are more prone to experience syncope compared with non-carriers and whether carriers have an increased mortality compared with non-carriers.

Methods And Results: All genetic variants previously associated with cLQTS were surveyed using the Human Gene Mutation Database.

Factors Associated With and Outcomes After Ventricular Fibrillation Before and During Primary Angioplasty in Patients With ST-Segment Elevation Myocardial Infarction.

We aimed to assess the risk factors and outcome of ventricular fibrillation (VF) before and during primary percutaneous coronary intervention (PPCI) in patients with ST-segment elevation myocardial infarction. From 1999 to 2012, we consecutively enrolled 5,373 patients with ST-segment elevation myocardial infarction. In total, 410 of the patients had VF before and 88 had VF during PPCI.

High incidence of functional ion-channel abnormalities in a consecutive Long QT cohort with novel missense genetic variants of unknown significance.

The Long QT syndrome (LQTS) is a disorder characterized by a prolongation of the QT interval and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death. Our objective was to (1) determine the incidence of variants with unknown significance (VUS) in a cohort of consecutive LQTS patients and (2) to determine the percentage of those with novel missense VUS that have demonstrable functional channel abnormalities from a single referral center. We performed genetic screening of candidate genes in 39 probands with a diagnosis of LQTS to identify mutations and variants.

Preservation of cardiac function by prolonged action potentials in mice deficient of KChIP2.

Inherited ion channelopathies and electrical remodeling in heart disease alter the cardiac action potential with important consequences for excitation-contraction coupling. Potassium channel-interacting protein 2 (KChIP2) is reduced in heart failure and interacts under physiological conditions with both Kv4 to conduct the fast-recovering transient outward K(+) current (Ito,f) and with CaV1.2 to mediate the inward L-type Ca(2+) current (ICa,L).

Protein kinase C-dependent regulation of connexin43 gap junctions and hemichannels.

Connexin43 (Cx43) generates intercellular gap junction channels involved in, among others, cardiac and brain function. Gap junctions are formed by the docking of two hemichannels from neighbouring cells. Undocked Cx43 hemichannels can upon different stimuli open towards the extracellular matrix and allow transport of molecules such as fluorescent dyes and ATP.

Gap junctions - guards of excitability.

Cardiomyocytes are connected by mechanical and electrical junctions located at the intercalated discs (IDs). Although these structures have long been known, it is becoming increasingly clear that their components interact. This review describes the involvement of the ID in electrical disturbances of the heart and focuses on the role of the gap junctional protein connexin 43 (Cx43).

Antiarrhythmic Effect of Either Negative Modulation or Blockade of Small Conductance Ca2+-activated K+ Channels on Ventricular Fibrillation in Guinea Pig Langendorff-perfused Heart.

During recent years, small conductance Ca-activated K (SK) channels have been reported to play a role in cardiac electrophysiology. SK channels seem to be expressed in atria and ventricles, but from a functional perspective, atrial activity is predominant. A general notion seems to be that cardiac SK channels are predominantly coming into play during arrhythmogenic events where intracellular concentration of Ca is increased.

P-wave duration and the risk of atrial fibrillation: Results from the Copenhagen ECG Study.

Background: Results on the association between P-wave duration and the risk of atrial fibrillation (AF) are conflicting.

Objective: The purpose of this study was to obtain a detailed description of the relationship between P-wave duration and the risk of AF.

Methods: Using computerized analysis of electrocardiograms from a large primary care population, we evaluated the association between P-wave duration and the risk of AF.

Sudden death in young persons with uncontrolled asthma--a nationwide cohort study in Denmark.

Background: Asthma is a common chronic disease among young adults, and several studies have reported increased mortality rates in patients with asthma. However, no study has described sudden unexpected death in a nationwide setting in patients with uncontrolled asthma. We defined uncontrolled asthma as a previous hospital admittance because of asthma (of any severity) or when asthma was considered to have influenced the death according to the death certificate.

Midline 1 controls polarization and migration of murine cytotoxic T cells.

Midline 1 (MID1) is a microtubule-associated ubiquitin ligase that regulates protein phosphatase 2 A levels. Loss-of-function mutations in MID1 lead to the human X-linked Opitz G/BBB (OS) syndrome characterized by defective midline development during embryogenesis. We have recently shown that MID1 is strongly up-regulated in murine cytotoxic T lymphocytes (CTLs), and that it has a significant impact on exocytosis of lytic granules and the killing capacity of CTLs.

Antiarrhythmic Mechanisms of SK Channel Inhibition in the Rat Atrium.

Introduction: SK channels have functional importance in the cardiac atrium of many species, including humans. Pharmacological blockage of SK channels has been reported to be antiarrhythmic in animal models of atrial fibrillation; however, the exact antiarrhythmic mechanism of SK channel inhibition remains unclear.

Objectives: We speculated that together with a direct inhibition of repolarizing SK current, the previously observed depolarization of the atrial resting membrane potential (RMP) after SK channel inhibition reduces sodium channel availability, thereby prolonging the effective refractory period and slowing the conduction velocity (CV).

Symptoms Before Sudden Arrhythmic Death Syndrome: A Nationwide Study Among the Young in Denmark.

Introduction: No studies in an unselected and nationwide setting have characterized the symptoms and medical history of patients with sudden arrhythmic death syndrome (SADS). The aim of this study was to identify and describe the symptoms and medical history of patients before the presentation of SADS.

Methods And Results: We have previously identified all of the autopsied sudden cardiac deaths (SCD; n = 314) in Danes aged 1-35 years between 2000 and 2006.

The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome.

Background: Sudden infant death syndrome (SIDS) is the most common cause of death in infants between the age of 1 month and 1 year. Rare variants in Nav1.5 encoded by SCN5A are known to play a role in SIDS; however, the combined role of the sodium current complex is unknown.

Common and rare variants in SCN10A modulate the risk of atrial fibrillation.

Background: Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r(2)=0.

Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study.

Aims: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration.

Methods And Results: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%).

Sympathetic vasoconstriction takes an unexpected pannexin detour.

Sympathetic vasoconstriction plays an important role in the control of blood pressure and the distribution of blood flow. In this issue of Science Signaling, Billaud et al. show that sympathetic vasoconstriction occurs through a complex scheme involving the activation of large-pore pannexin 1 channels and the subsequent release of adenosine triphosphate that promotes contraction in an autocrine and paracrine manner.

Risk factors and causes of sudden noncardiac death: A nationwide cohort study in Denmark.

Background: On the performance of an autopsy, sudden deaths may be divided into 2 classifications: (1) sudden cardiac deaths and (2) sudden noncardiac deaths (SNCDs). Families of SNCD victims should not be followed up as a means of searching for cardiac disease.

Objective: The purpose of this study was to report the risk factors and causes of SNCD.

Incidence and risk factors of ventricular fibrillation before primary angioplasty in patients with first ST-elevation myocardial infarction: a nationwide study in Denmark.

Background: We aimed to investigate the incidence and risk factors for ventricular fibrillation (VF) before primary percutaneous coronary intervention (PPCI) among patients with ST-segment elevation myocardial infarction (STEMI) in a prospective nationwide setting.

Methods And Results: In this case-control study, patients presenting within the first 12 hours of first STEMI who survived to undergo angiography and subsequent PPCI were enrolled. Over 2 years, 219 cases presenting with VF before PPCI and 441 controls without preceding VF were enrolled.