Aging of the heart is associated with a blunted response to sympathetic stimulation, reduced contractility, and increased propensity for arrhythmias, with the risk of sudden cardiac death ...significantly increased in the elderly population. The altered cardiac structural and functional phenotype, as well as age-associated prevalent comorbidities including hypertension and atherosclerosis, predispose the heart to atrial fibrillation, heart failure, and ventricular tachyarrhythmias. At the cellular level, perturbations in mitochondrial function, excitation-contraction coupling, and calcium homeostasis contribute to this electrical and contractile dysfunction. Major determinants of cardiac contractility are the intracellular release of Ca
from the sarcoplasmic reticulum by the ryanodine receptors (RyR2), and the following sequestration of Ca
by the sarco/endoplasmic Ca
-ATPase (SERCa2a). Activity of RyR2 and SERCa2a in myocytes is not only dependent on expression levels and interacting accessory proteins, but on fine-tuned regulation via post-translational modifications. In this paper, we review how aberrant changes in intracellular Ca
cycling via these proteins contributes to arrhythmogenesis in the aged heart.
The evaluation of the fracture toughness of tungsten is required for the design of plasma-facing components in order to ensure safe and durable operation in ITER reactor, being under construction in ...France. During operation, plasma facing materials will be exposed to cyclic thermo-mechanical loads combined with high energy neutron flux, which, in general, reduce the fracture toughness. Characterization of the degradation of the mechanical properties after exposure to the neutron flux involves time consuming and expensive procedures due to nuclear activation and special handling. Subsequently, development of sample miniaturization and protocols to reduce the volume of material under inspection is critical to speed up the progress in R&D. In this work, we propose a combined approach for the reconstruction of the fracture toughness – temperature curve, which is applied in the ductile to brittle transition temperature range. The approach consists of two steps: (i) application of the three point bending tests using miniaturized samples to reveal the transition temperature range on the basis of flexural strain data; (ii) execution of standardized fracture toughness tests at the upper temperature of the transition regime. The results allow the determination of the fracture toughness as a function of temperature with a reasonable accuracy. The validity of the approach has been demonstrated on two commercial tungsten grades produced according to ITER specification and tested in the as-fabricated state. The conclusions are supported by microstructural analysis performed on both standardized and miniaturized samples.
A rapid growth in the incidence of diabetes and obesity has transpired to a major heath issue and economic burden in the postindustrial world, with more than 29 million patients affected in the ...United States alone. Cardiovascular defects have been established as the leading cause of mortality and morbidity of diabetic patients. Over the last decade, significant progress has been made in delineating mechanisms responsible for the diminished cardiac contractile function and enhanced propensity for malignant cardiac arrhythmias characteristic of diabetic disease. Rhythmic cardiac contractility relies upon the precise interplay between several cellular Ca
transport protein complexes including plasmalemmal L-type Ca
channels (LTCC), Na
-Ca
exchanger (NCX1), Sarco/endoplasmic Reticulum (SR) Ca
-ATPase (SERCa2a) and ryanodine receptors (RyR2s), the SR Ca
release channels. Here we provide an overview of changes in Ca
homeostasis in diabetic ventricular myocytes and discuss the therapeutic potential of targeting Ca
handling proteins in the prevention of diabetes-associated cardiomyopathy and arrhythmogenesis.
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. In recent years ER stress has become recognized as an important contributing factor in many cardiac pathologies, including deadly ventricular arrhythmias. This brief review will therefore focus on ER stress mechanisms in the heart and how these changes can lead to pro-arrhythmic defects in SR Ca
handling machinery.
Sudden cardiac death due to malignant ventricular arrhythmias remains the major cause of mortality in the postindustrial world. Defective intracellular Ca
2+
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
2+
homeostasis which substantially increases arrhythmic risk. This brief review will focus on functional changes in elements of Ca
2+
handling machinery in cardiomyocytes that occur secondary to genetic mutations associated with catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome.
Tungsten (W) based materials for fusion reactor applications have been developed in Japan for the last decade to improve thermo-mechanical properties and tolerance with respect to neutron-irradiation ...effects. Potassium (K) doping for dispersion strengthening and alloying by rhenium (Re) for solid solute softening and strengthening were applied to W fabricated by powder metallurgy. Thereby modified W materials, e.g. K-doped W and K-doped W-3%Re, demonstrated a higher recrystallization temperature threshold, an increase in strength and ductility, and a reduction in ductile-to-brittle transition temperature (DBTT) compared to pure W in the non-irradiated state. Embrittlement caused by displacement damage and its amplification due to solid transmutation products is expected to be an intrinsic issue of W based materials under neutron irradiation environment inherent to future fusion reactors. In this paper, the effect of K-doping and alloying by Re on the neutron-irradiation-induced embrittlement of W was investigated at neutron fluence causing a considerable amount of solid transmutation products.
The strength and ductility of two tungsten products, developed for application in nuclear fusion environment, are studied before and after neutron irradiation using uniaxial tensile tests. The first ...product is a commercially pure tungsten, produced by AT&M company according to ITER specification, and the second one is reinforced with zirconium carbide (W–ZrC) particles. The addition of ZrC particles leads to a reduction of the ductile to brittle transition temperature (DBTT) in non-irradiated conditions down to 50–100 °C without loss of strength and of other attractive properties of tungsten.
The neutron irradiation was performed in the range 625–700 °C up to 1.125 dpa. The tests were performed to screen the shift of the DBTT as well as to characterize the evolution of the strength and ductility at the irradiation temperature. In addition, a series of interrupted tensile tests were performed in order to determine the variation of the yield strength as a function of temperature using an original single specimen test method.
The neutron irradiation causes the reduction of the total elongation of both tungsten products. The DBTT range, which was evaluated from the tensile test results, of W–ZrC lies in the 300–500 °C range (while it is ∼100 °C in non-irradiated state). The DBTT range of pure tungsten is between 400 and 575 °C i.e. higher than that of W–ZrC. The irradiation hardening, measured at ∼600 °C, which is close to the irradiation temperature, leads to an increase of the proof stress by a factor of two in both studied grades. Despite that the irradiation induced hardening, both products retain a total elongation of about 10% prior to fracture. W–ZrC exhibits a similar total elongation at 500 °C, thus maintaining a significant ductility resource, while pure W becomes brittle at 500 °C and below.
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. For the defects with dislocation character, the following ordering of the interaction strength was established: H < N < C < O < He. The magnitude of the interaction energy was rationalized by decomposing it into elastic (related to the lattice strain) and chemical (related to local electron density) contributions. To account for the combined effect of impurity concentration and pinning strength, the impact of the presence of these impurities on the mobility of isolated dislocation loops was studied for DEMO relevant conditions in the non-elastic and dilute limit.
Cardiac disease is associated with deleterious emission of mitochondrial reactive oxygen species (mito-ROS), as well as enhanced oxidation and activity of the sarcoplasmic reticulum (SR) Ca
2+
...release channel, the ryanodine receptor (RyR2). The transfer of Ca
2+
from the SR via RyR2 to mitochondria is thought to play a key role in matching increased metabolic demand during stress. In this study, we investigated whether augmented RyR2 activity results in self-imposed exacerbation of SR Ca
2+
leak, via altered SR-mitochondrial Ca
2+
transfer and elevated mito-ROS emission. Fluorescent indicators and spatially restricted genetic ROS probes revealed that both pharmacologically and genetically enhanced RyR2 activity, in ventricular myocytes from rats and catecholaminergic polymorphic ventricular tachycardia (CPVT) mice, respectively, resulted in increased ROS emission under β-adrenergic stimulation. Expression of mitochondrial Ca
2+
probe mtRCamp1h revealed diminished net mitochondrial Ca
2+
with enhanced SR Ca
2+
leak, accompanied by depolarization of the mitochondrial matrix. While this may serve as a protective mechanism to prevent mitochondrial Ca
2+
overload, protection is not complete and enhanced mito-ROS emission resulted in oxidation of RyR2, further amplifying proarrhythmic SR Ca
2+
release. Importantly, the effects of augmented RyR2 activity could be attenuated by mitochondrial ROS scavenging, and experiments with dominant-negative paralogs of the mitochondrial Ca
2+
uniporter (MCU) supported the hypothesis that SR-mitochondria Ca
2+
transfer is essential for the increase in mito-ROS. We conclude that in a process whereby leak begets leak, augmented RyR2 activity modulates mitochondrial Ca
2+
handling, promoting mito-ROS emission and driving further channel activity in a proarrhythmic feedback cycle in the diseased heart.
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