Riluzole is associated with reduced risk of heart failure.

Background: Reduction of intracellular Na accumulation through late Na current inhibition has been recognized as a target for cardiac Ca handling which underlies myocardial contractility and relaxation in heart failure (HF). Riluzole, an Na channel blocker with enhancement of Ca-activated K channel function, used for management of amyotrophic lateral sclerosis (ALS), is effective in suppressing Ca leak and therefore may improve cardiac function.

Objectives: The study aim was to investigate whether riluzole lowers HF incidence.

Reduction in activity and abundance of mitochondrial electron transport chain supercomplexes in pulmonary hypertension-induced right ventricular dysfunction.

Pulmonary hypertension (PH) results in RV hypertrophy, fibrosis and dysfunction resulting in RV failure which is associated with impaired RV metabolism and mitochondrial respiration. Mitochondrial supercomplexes (mSC) are assemblies of multiple electron transport chain (ETC) complexes that consist of physically associated complex I, III and IV that may enhance respiration and lower ROS generation. The goal of this study was to determine if mSCs are reduced in RV dysfunction associated with PH.

Maternal exercise preserves offspring cardiovascular health via oxidative regulation of the ryanodine receptor.

Objective: The intrauterine environment during pregnancy is a critical factor in the development of obesity, diabetes, and cardiovascular disease in offspring. Maternal exercise prevents the detrimental effects of a maternal high fat diet on the metabolic health in adult offspring, but the effects of maternal exercise on offspring cardiovascular health have not been thoroughly investigated.

Methods: To determine the effects of maternal exercise on offspring cardiovascular health, female mice were fed a chow (C; 21% kcal from fat) or high-fat (H; 60% kcal from fat) diet and further subdivided into sedentary (CS, HS) or wheel exercised (CW, HW) prior to pregnancy and throughout gestation.

Loss of YTHDF2 Alters the Expression of mA-Modified Myzap and Causes Adverse Cardiac Remodeling.

How post-transcriptional regulation of gene expression, such as through -methyladenosine (mA) messenger RNA methylation, impacts heart function is not well understood. We found that loss of the mA binding protein YTHDF2 in cardiomyocytes of adult mice drove cardiac dysfunction. By proteomics, we found myocardial zonula adherens protein (MYZAP) within the top up-regulated proteins in knockout cardiomyocytes.

Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart.

Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases.

STIM1 ablation impairs exercise-induced physiological cardiac hypertrophy and dysregulates autophagy in mouse hearts.

Cardiac stromal interaction molecule 1 (STIM1), a key mediator of store-operated Ca entry (SOCE), is a known determinant of cardiomyocyte pathological growth in hypertrophic cardiomyopathy. We examined the role of STIM1 and SOCE in response to exercise-dependent physiological hypertrophy. Wild-type (WT) mice subjected to exercise training (WT-Ex) showed a significant increase in exercise capacity and heart weight compared with sedentary (WT-Sed) mice.

NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling.

Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na+ (NaV) and L-type Ca2+ channels (LTCCs). LTCC dysregulation by mutant CaMs has been implicated in action potential duration (APD) prolongation and arrhythmogenic long QT (LQT) syndrome. Intriguingly, D96V-CaM prolongs APD more than other LQT-associated CaMs despite inducing comparable levels of LTCC dysfunction, suggesting dysregulation of other depolarizing channels.

ER stress and calcium-dependent arrhythmias.

The sarcoplasmic reticulum (SR) plays the key role in cardiac function as the major source of Ca that activates cardiomyocyte contractile machinery. Disturbances in finely-tuned SR Ca release by SR Ca channel ryanodine receptor (RyR2) and SR Ca reuptake by SR Ca-ATPase (SERCa2a) not only impair contraction, but also contribute to cardiac arrhythmia trigger and reentry. Besides being the main Ca storage organelle, SR in cardiomyocytes performs all the functions of endoplasmic reticulum (ER) in other cell types including protein synthesis, folding and degradation.

Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia.

Background: Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca homeostasis, impairing luminal Ca regulation of the sarcoplasmic reticulum (SR) Ca release channel, the RyR2 (ryanodine receptor), and increasing channel activity. However, exact mechanisms underlying redox-mediated increase of RyR2 function in cardiac disease remain elusive. We tested whether the oxidoreductase family of proteins that dynamically regulate the oxidative environment within the SR are involved in this process.

Acute Detubulation of Ventricular Myocytes Amplifies the Inhibitory Effect of Cholinergic Agonist on Intracellular Ca Transients.

Muscarinic receptors expressed in cardiac myocytes play a critical role in the regulation of heart function by the parasympathetic nervous system. How the structural organization of cardiac myocytes affects the regulation of Ca handling by muscarinic receptors is not well-defined. Using confocal Ca imaging, patch-clamp techniques, and immunocytochemistry, the relationship between t-tubule density and cholinergic regulation of intracellular Ca in normal murine ventricular myocytes and myocytes with acute disruption of the t-tubule system caused by formamide treatment was studied.

MCU overexpression evokes disparate dose-dependent effects on mito-ROS and spontaneous Ca release in hypertrophic rat cardiomyocytes.

Cardiac dysfunction in heart failure (HF) and diabetic cardiomyopathy (DCM) is associated with aberrant intracellular Ca handling and impaired mitochondrial function accompanied with reduced mitochondrial calcium concentration (mito-[Ca]). Pharmacological or genetic facilitation of mito-Ca uptake was shown to restore Ca transient amplitude in DCM and HF, improving contractility. However, recent reports suggest that pharmacological enhancement of mito-Ca uptake can exacerbate ryanodine receptor-mediated spontaneous sarcoplasmic reticulum (SR) Ca release in ventricular myocytes (VMs) from diseased animals, increasing propensity to stress-induced ventricular tachyarrhythmia.

Impact of interstitial impurities on the trapping of dislocation loops in tungsten.

Ab initio simulations are employed to assess the interaction of typical interstitial impurities with self-interstitial atoms, dislocation loops and edge dislocation lines in tungsten. These impurities are present in commercial tungsten grades and are also created as a result of neutron transmutation or the plasma in-take process. The relevance of the study is determined by the application of tungsten as first wall material in fusion reactors.

Sarcoplasmic reticulum-mitochondria communication; implications for cardiac arrhythmia.

Sudden cardiac death due to ventricular tachyarrhythmias remains the major cause of mortality in the world. Heart failure, diabetic cardiomyopathy, old age-related cardiac dysfunction and inherited disorders are associated with enhanced propensity to malignant cardiac arrhythmias. Both defective mitochondrial function and abnormal intracellular Ca homeostasis have been established as the key contributing factors in the pathophysiology and arrhythmogenesis in these conditions.

New insights into microstructure of neutron-irradiated tungsten.

The development of appropriate materials for fusion reactors that can sustain high neutron fluence at elevated temperatures remains a great challenge. Tungsten is one of the promising candidate materials for plasma-facing components of future fusion reactors, due to several favorable properties as for example a high melting point, a high sputtering resistivity, and a low coefficient of thermal expansion. The microstructural details of a tungsten sample with a 1.

Pyridostigmine improves cardiac function and rhythmicity through RyR2 stabilization and inhibition of STIM1-mediated calcium entry in heart failure.

Heart failure (HF) is characterized by asymmetrical autonomic balance. Treatments to restore parasympathetic activity in human heart failure trials have shown beneficial effects. However, mechanisms of parasympathetic-mediated improvement in cardiac function remain unclear.

Interleukin-1β, Oxidative Stress, and Abnormal Calcium Handling Mediate Diabetic Arrhythmic Risk.

Diabetes mellitus (DM) is associated with increased arrhythmia. Type 2 DM (T2DM) mice showed prolonged QT interval and increased ventricular arrhythmic inducibility, accompanied by elevated cardiac interleukin (IL)-1β, increased mitochondrial reactive oxygen species (mitoROS), and oxidation of the sarcoplasmic reticulum (SR) Ca release channel (ryanodine receptor 2 [RyR2]). Inhibiting IL-1β and mitoROS reduced RyR2 oxidation and the ventricular arrhythmia in DM.

The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes.

Sudden cardiac death due to malignant ventricular arrhythmias remains the major cause of mortality in the postindustrial world. Defective intracellular Ca homeostasis has been well established as a key contributing factor to the enhanced propensity for arrhythmia in acquired cardiac disease, such as heart failure or diabetic cardiomyopathy. More recent advances provide a strong basis to the emerging view that hereditary cardiac arrhythmia syndromes are accompanied by maladaptive remodeling of Ca homeostasis which substantially increases arrhythmic risk.

Depth-Sensing Hardness Measurements to Probe Hardening Behaviour and Dynamic Strain Ageing Effects of Iron during Tensile Pre-Deformation.

This work reports results from quasi-static nanoindentation measurements of iron, in the un-strained state and subjected to 15% tensile pre-straining at room temperature, 125 °C and 300 °C, in order to extract room temperature hardness and elastic modulus as a function of indentation depth. The material is found to exhibit increased disposition for pile-up formation due to the pre-straining, affecting the evaluation of the mechanical properties of the material. Nanoindentation data obtained with and without pre-straining are compared with bulk tensile properties derived from the tensile pre-straining tests at various temperatures.

Impact of I Voltage and Ca/Mg-Dependent Rectification on Cardiac Repolarization.

Cardiac small conductance Ca-activated K (SK) channels are activated solely by Ca, but the SK current (I) is inwardly rectified. However, the impact of inward rectification in shaping action potentials (APs) in ventricular cardiomyocytes under β-adrenergic stimulation or in disease states remains undefined. Two processes underlie this inward rectification: an intrinsic rectification caused by an electrostatic energy barrier from positively charged amino acids at the inner pore and a voltage-dependent Ca/Mg block.

Late I Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2.

Background: Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (I) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs.

Methods: We tested the effects of the selective I blocker GS967 on PVT induction in a transgenic rabbit model of long QT syndrome type 2 using intact heart optical mapping, cellular electrophysiology and confocal Ca imaging, and computer modeling.