bluuebunny/crossref_metadata_2025 huggingface dataset:
Determination of Casting Parameters for Affirmative Directional Solidification in 750 KW Francis Runner
Authors: Kafle Abishek , Sapkota Nishan , Silwal Raman , Shrestha Pratisthit Lal , Sharma Nischal , Thapa Bhola
Published: June 2022

Entangled by a web-like pattern of rivers and rivulets, Nepal’s energy sector currently is dominated by hydroelectricity which sustains a major portion of the country’s economy. But still, after more than a hundred years of its operation, the sector’s dependence on imports is uncanny. This not only upsizes the project cost but also the time and human resources. The research, therefore, aims to aid the cause by examining the prospect of manufacturing runners using local industrial expertise in synchronization with available data and research. Here, the paper focuses on the sand casting of a 750KW Francis runner and the design of its parameters namely gating and feeding system to ensure directional solidification. Apart from the conventional procedure, the casting of the runner was proceeded as three separate parts: hub, shroud, and blade which were later welded together. The gate and riser placement for each of the parts was designed independently and analysed for any shrinkage porosities and possible voids using computer simulation with several iterations each. Specifically, temperature variations during three major stages of solidification assigned as 0, 50, and 100 were tested for a total of 195 nodes. The design was then transferred into the mould and casting was performed. The procedure resulted in a cast with a clean surface finish and minimal visible defects. The study, thus, suggests the possibility of manufacturing runners through metal casting and its substantial implications in the improvement of the hydropower industry in Nepal.
Rapid Analysis of Cylindrical Bypass Flow Field Based on Deep Learning Model
Authors: Jian L , Huang Z , Zhang J , Hu Z
Published: June 2022

Deep learning models provide a novel research perspective for hydraulic machinery and fluid dynamics mechanism research. Traditional computational fluid dynamics requires a lot of computational resource and calculation time, while deep learning models can effectively solve this problem. In this paper, a deep learning model is proposed for the rapid flow field analysis of a two-dimensional cylindrical bypass flow, and the errors of the prediction results are analyzed, so as to verify the feasibility of deep learning for accelerating the numerical simulation process. On this basis, the influence of different network structures on the prediction performance of the deep learning model is explored, and the optimal structural parameters of the neural network are found, indicating that it will achieve real-time prediction of the flow field performance, and save considerable computational resource and calculation time. The research in this paper is of great significance for the application about the rapid analysis of hydraulic machinery fluid dynamics based on deep learning models.
Development of simplified model for prediction of sediment induced erosion in Francis turbine’s sidewall gaps
Authors: Acharya Nirmal , Gautam Saroj , Chitrakar Sailesh , Dahlhaug Ole Gunnar
Published: June 2022

Sediment induced erosion in exposed components of hydraulic turbines is a major issue in most of the sediment laden hydropower projects. Gradual removal of material can change the components profile which can lead to change in flow characteristics and compromise in the efficiency as well. Among several components in Francis turbine, this study focuses on the runner sidewall gaps to develop a numerical model for erosion prediction. A prototype high head Francis runner with specific speed of 85.4 rpm has been considered as the reference case. A simplified numerical model based on the concept of rotating disc apparatus (RDA) is conceptualized to make analogy with the gap available between runner blades and guide vanes (GVs). Fillet gaps are introduced in the model to emulate the gaps available between runner blade and GV for real case scenario. Four samples with 90° separation of each are mounted on the disc rotating at 750 rpm. Sediment size of 150 μm diameter with particle mass flow rate based on the maximum amount of sediment passing through the reference turbine is used. Numerical calculation is done in ANSYS® with Tabakoff erosion model. Results give an indication of critical zones in the gap region. Erosion pattern, rate density and vorticity are compared with the actual turbine.
Critical speed analysis of the shafting rotor of the vertical long shaft fire pump under the different positions of the impellers
Authors: Fu L H , Yang Z J , Jin S B , Zhang J F , Song H Q , Yu X H , Zhang W J , Li G D
Published: June 2022

For multi-stage pumps, the change of the impeller stage spacing will have a greater impact on the dynamic characteristics of the shafting rotor. The paper took XBC18-178-240LC3 vertical long shaft fire pump as the research object, using ANSYS Workbench software to study the relationship between the critical speed of the shafting rotor and the different positions of the impellers. First, 9 shafting rotors (based Z4,Z5 and Z6 models) under the different positions of the impellers were established; and then the change law of the critical speed on 9 shafting rotors in the first 12 modes was studied. The results showed that different positions of the impeller on the shaft have a great impact on critical speed of the shafting rotor. With the increase of the distance between the impeller stages, the low-order critical speed (6th order and within) of the Z4 model shafting rotor decreases. However, the low-order critical speed (5th order and within) of the Z5 and Z6 model shafting rotors decreases with the increase of the distance between the impeller stages, and the high-order critical speed doesn’t satisfy this law. Considering static characteristics of the shafting rotor and actual engineering applications, the paper selected the Z5-stage spacing 800mm shafting rotor model as the best case, providing a theoretical support for the subsequent vertical long shaft fire pump design optimization.
Influence of Rotor Geometry on Cavitation Characteristics of Rotational Hydrodynamic Cavitation Generator
Authors: Wang X , Xie C , Zhang W , Meng G Q Q G
Published: June 2022

The RNG k-ε turbulence model and mass transport cavitation model are applied to simulate the cavitating flows in a rotational hydrodynamic cavitation generator with a rotor and a stator. The cavitation generator is designed to have surface dimples on the rotor. The cavitating flows analyses in cavitation generator are focused mainly in the rotor. The accuracy and reliability of the calculation model and method are demonstrated by the good agreement between with experimental and numerical results. The pressure distribution, streamline distribution and vapor volume fraction distribution in cavitation generator with five different structures (5 different diameter of rotor dimples d=11mm, 13mm, 15mm, 17mm, 19mm) under the same operation condition are analysed. The calculation results show that the characteristics of streamline and cavitaion area and pressure area are quite different based on the magnitude of the dimple diameter of the rotor. It is observed that with the rotor dimple diameter increase, the cavity bubbles firstly appear in the low pressures area of dimple bottom and develops rapidly towards the wall and top of dimple; the mass transfer between water and vapor is even more intense; the low pressures area increases in dimple and the vortex area expands and the number of vortices increases, which induces the strong turbulence on the surface of the rotor and inside the rotor. The increasing the diameter of the rotor dimple is an effective means to enhance the cavitation effect of the rotational hydrodynamic cavitation generator.
A review on erosion and erosion induced vibrations in Francis turbine
Authors: Shrestha Rakish , Pradhan Samman Singh , Gurung Prithivi , Ghimire Amul , Chitrakar Sailesh
Published: June 2022

Vibrations are one of the major issues observed during the operations of Francis turbine as they are frequently operated outside their optimal operating range, with rapid load changes. In hydropower plants, vibrations occur in various parts which can be classified as: hydraulic civil parts such as reservoir, intake, dam, tail race etc. mechanical parts such as penstock, turbine, draft tube and shaft, and electrical parts such as generator and transformer. However, due to the sediments and cavitation problems, the regions around rotating parts such as turbine experiences severe vibration. In the cases where the turbines need to be operated with high sediment load, the vibration problems could be further aggravated due to sediment carrying flow and declination of the surface morphology after erosion. This paper is based on a literature review to explore the characteristic effects of erosion and cavitation which could result in losses, vibrations, fatigues on the turbine materials and oblivious turbine failure. The study aims to correlate the erosion and cavitation due to abrasion with the pressure fluctuations resulting in vibrations.
Comparative analysis of flow characteristics of different blade inclination outlet schemes of long shaft pumps
Authors: Zhang J F , Zhang W J , Jin S B , Yang Z J , Jin C M , Fu L H , Yu X H , Li G D
Published: June 2022

Multistage space guide vane long shaft pump is widely used in many important fields because of its compact structure, convenient maintenance and simple pipeline. However, due to the complex flow phenomenon in its channel, the space guide vane long shaft pump has the problem of low performance. This paper takes xb4.3/240-300lc vertical long shaft fire pump as the research object. When the blade outlet width is the same, three schemes of impeller outlet inclination angle (0°, 15°and 25°) are designed, and CFX is used for numerical simulation to analyse the difference of internal flow field of each scheme. The results show that compared with the other two schemes, the scheme with an inclination angle of 15° has better performance in efficiency(
η
) and head(
H
). The pressure on the working surface of the blade is higher than that on the back of the blade, and the pressure near the front cover plate increases with the growth of the inclination angle. Under the condition of small flow, the velocity at the impeller outlet increases with the growth of inclination angle. Under the condition of large flow, the velocity at the impeller outlet decreases with the growth of inclination angle. Similarly, the turbulent kinetic energy shares the same pattern with the velocity at the impeller outlet. Under all working conditions, small vortex structure appears in impeller and guide vane. It is found that the scheme with impeller outlet inclination angle of 15° has smaller impeller vortex structure under standard working condition.
Investigation on the Flow Characteristics of Complex Flow Channel System of Mixed-flow Pump with Impulse Operation
Authors: Sun Mingkang , Xu Jin , Huang Chuibing , Zhang Xiaoping , Huang Zhenwei
Published: June 2022

How to construct a turbulence model applicable to the flow characteristics of complex flow channel system in mixed-flow pump with impulse operation is of great importance, both for the numerical simulation accuracy of complex flow channels and the subsequent study of transient flow mechanism. In this paper, based on the closure parameters Cε2
and Cμ
, a new turbulence model is proposed for the study on flow characteristics of complex flow channel system in mixed-flow pump with impulse operation. Experimental measurement and numerical calculation reveal that the closure parameters Cε2
and Cμ
in the turbulence model have an important impact on the calculation accuracy compared with other closure parameters. The results indicate that appropriate reduction of the two parameters can effectively promote the calculation precision. Compared with the traditional turbulence model, the maximum error in the numerical calculation of the new turbulence model is reduced by 30%. The research in this paper lays the theoretical foundation for the transient flow mechanism of complex flow channel system in mixed-flow pump with impulse operation.
Numerical Investigation on Suitable Flow Guide for Performance Enhancement of Darrieus-type Hydraulic Turbine by 2-D Simulation
Authors: Mayuzumi Y , Katayama Y , Watanabe S , Tsuda S
Published: June 2022

The aim of this investigation is improvement of the performance of Darrieus-type hydraulic turbines operated in an open channel. Since the output power is very small in such a utilization of small hydropower, it is important to get more power for the cost reduction. In our previous experimental investigation, the performance of turbine runner installed near the side wall of the channel was better than that installed at the center of the channel. In order to enhance the output power, a flat guide was installed upstream of the runner on the opposite side of the side wall. In the present study, we parametrically investigate the effects of flow guiding angle and installation position of the guide on the turbine performance. Two-dimensional unsteady CFD simulations are carried out to qualitatively understand the flow mechanism leading to the better performance of turbine. As a result, it is found that the turbine performance can be significantly enhanced by the appropriately placed flow guide. This enhancement is found to be achieved by the improvement of turbine efficiency and the increase of the input power.
Numerical investigation of a Pelton turbine at several operating conditions
Authors: Gautam Saroj , Chitrakar Sailesh , Neopane Hari Prasad , Solemslie Bjørn W , Dahlhaug Ole Gunnar
Published: June 2022

The use of Computational Fluid Dynamics (CFD) for predicting the flow behaviour in Pelton turbines is limited by the complex nature of the flow, interaction between the jets and interference of the water after the impact on the buckets. Besides, validation of the numerical results in such turbines is usually challenging due to the unsteadiness of the flow properties. Hence, time-dependent analysis with multi-phase models is required for obtaining such solutions. This paper conducts a CFD analysis on a Pelton turbine using RANS based Eulerian scheme. The fluid domain consists of three successive buckets placed in their corresponding circumferential locations, along with a spear valve, which is adjusted for various operating conditions. Such a domain assumes that the interaction of the jet on the buckets takes place for a maximum of three buckets at any particular time. The results of the CFD analysis are compared with the experimental results for all the studied opening conditions. The objective of this work is to build a suitable numerical model that can be applied to any Pelton turbines, such that a complete performance curve of the turbine can be generated. The flow pattern between entry and exit of the bucket obtained from CFD is compared with images taken from a high speed camera in rotating frame of reference. The results of the numerical analysis are found to be in a good agreement with the experimental data.
Parametric modeling of re-electrification by green hydrogen as an alternative to backup power
Authors: Subedi A , Thapa B S
Published: June 2022

Electricity backup systems are needed to address the temporary grid failure, short-term electricity supply at the locations without grids, power surges, and massive blackouts. These power backup technologies include a combination of batteries and generators operating mostly on fossil fuels. Concerns regarding instant start capability with generators, noise, and mainly due to carbon emissions have encouraged to look for alternatives with low carbon technologies based on renewable energy sources. Stored electricity from solar, wind and other renewable sources are emerging and cost-competitive alternatives to fossil fuels-based power backup systems. Due to the high energy density, unlimited production source, and easy storage and transportation, hydrogen is emerging as an effective and efficient energy carrier and its applications for an alternative to power supply systems. Hydrogen produced from the electrolysis of water by renewable electricity makes it green and has minimum carbon emissions among the other alternatives and operates in real-time startups with no mechanical noise.

Fuel cell is a growing technology and has the potential to channelize hydrogen energy as an alternative to carbon-intensive power supply systems. In a fuel cell, hydrogen combines with oxygen and produces electricity. The fuel cell is a robust design with several parameters that control its operation and capacity. This paper identifies the parameter-based modeling approach to establish a connection of power demand with hydrogen production. A mathematical model for system sizing of hydrogen production and fuel cell for re-electrification for a reference case is developed.
Effect of Mechanical Vibration in a Power House Located in the Nepal Himalaya
Authors: Chhushyabaga B , Karki S , Khadka S S
Published: June 2022

Design of powerhouse is a major concern in hydropower project located in Nepal Himalaya. Nepal is located in seismically active zone. The structures built in this region have to be seismic resistant in addition to dynamic loads, produced in power house due to the vibration of turbine and generator set. The structural elements of the power such as slab, column, foundation, wind cover, wall need to sustain produced vibration. It should also be earthquake resistant at the same time. Using finite element methods, the transmission of the produced vibration in powerhouse was analyzed for a selected case study located in lesser Himalaya of Nepal. The nature transfer of vibration loads through all the supporting structure beam, column, foundation raft is analyzed. The critical nature and path of energy transfer due to dynamic load was recognized in terms of the displacement produced with the comparative study in the model without mechanical vibrations.
Co-production of schizophyllan and cellulolytic enzymes from bagasse by Schizophyllum commune
Authors: Arunrattanamook Nattapol , Sornlake Warasirin , Champreda Verawat
Published: June 2022

Schizophyllum commune is a mushroom-forming fungus well-known for its ability to degrade lignocellulosic materials and production of schizophyllan, a high added-value product for cosmeceutical, pharmaceutical, and biomaterial industries. Conventionally, schizophyllan is produced by submerged fermentation using glucose as a carbon source. In this work, we demonstrate that alkaline pretreated bagasse can be used by Schizophyllum commune as an alternative carbon source for the production of schizophyllan. The influence of different factors was investigated including cultivation time, biomass loading, and culturing media component and a co-product correlation model was proposed. In this lab-scale study, a yield of 4.4 g/L of schizophyllan containing 89% glucose was achieved. In addition to schizophyllan, the cellulolytic enzymes co-produced during this process were isolated and characterized and could find applications in a range of industrial processes. This demonstrates the potential of using agricultural waste as a cheaper alternative feedstock for this biorefinery process.
Exposure Outcomes in Fully Vaccinated Healthcare Personnel With Known Severe Acute Respiratory Syndrome Coronavirus 2 Exposure—Minnesota, January–August 2021
Authors: Ruhland Abbey , Fell Ashley , Holzbauer Stacy M , D’Heilly Paige , Curtis Kris , Wick Holly , Friedman Bree , Mumm Erica , Ireland Malia , Estey-Dix Carrie , Betts-Roelike Melissa , Beaudoin Amanda
Published: June 2022

Healthcare personnel (HCP) are at potential risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in occupational and nonoccupational settings, even when fully vaccinated. This risk increased during Delta variant circulation. SARS-CoV-2 testing of fully vaccinated HCP working in the 14 days after exposure is important to prevent virus introduction into healthcare settings.
Broad Antimicrobial Resistance in a Case of Relapsing Babesiosis Successfully Treated With Tafenoquine
Authors: Rogers Ralph , Krause Peter J , Norris Ashlyn M , Ting Michelle H , Nagami Ellen H , Cilley Brian , Vannier Edouard
Published: June 2022

We describe a case of relapsing babesiosis in an immunocompromised patient. A point mutation in the Babesia microti 23S rRNA gene predicted resistance to azithromycin and clindamycin, whereas an amino acid change in the parasite cytochrome b predicted resistance to atovaquone. Following initiation of tafenoquine, symptoms and parasitemia resolved.
Walras, a novel lncRNA linked to cardiomyocyte cytoarchitecture and atrial fibrillation
Authors: Franco D , Dominguez J , Lodde V , Munk R , Abdelmohsen K , Gorospe M , Jimenez-Sabado V , Ginel A , Hove-Madsen L , Aranega A , Garcia-Padilla C
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Junta de Andalucia

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in humans. Genetic and genomic analyses have recently demonstrated that the homeobox transcription factor Pitx2 plays a fundamental role regulating expression of distinct growth factors, microRNAs and ion channels leading to morphological and molecular alterations that promote the onset of AF. Here we address the plausible contribution of long non-coding (lnc)RNAs within the Pitx2>Wnt>miRNA signaling pathway. In silico analyses of annotated lncRNAs in the vicinity of the Pitx2, Wnt8 and Wnt11 chromosomal loci identified five novel lncRNAs with differential expression during cardiac development. Importantly, three of them, Walaa, Walras and Wallrd, are evolutionarily conserved in humans and displayed preferential atrial expression during embryogenesis. In addition, Walrad displayed moderate expression during embryogenesis but was more abundant in the right atrium. Walaa, Walras and Wallrd were distinctly regulated by Pitx2, Wnt8, and Wnt11, and Wallrd was severely elevated in conditional atrium-specific Pitx2-deficient mice. Furthermore, pro-arrhythmogenic and pro-hypertrophic substrate administration to primary cardiomyocyte cell cultures consistently modulate expression of these lncRNAs, supporting distinct modulatory roles of the AF cardiovascular risk factors in the regulation of these lncRNAs. Walras affinity pulldown assays revealed its association with distinct cytoplasmic and nuclear proteins previously involved in cardiac pathophysiology, while loss-of-function assays further support a pivotal role of this lncRNA in cytoskeletal organization. We propose that lncRNAs Walaa, Walras and Wallrd, distinctly regulated by Pitx2>Wnt>miRNA signaling and pro-arrhythmogenic and pro-hypertrophic factors, are implicated in atrial arrhythmogenesis, and Walras additionally in cardiomyocyte cytoarchitecture.
Telomerase and myocardin co-expressing mesenchymal cells increase survival and induce cardiac and vascular markers in cardiac stromal cells undergoing simulated ischemia/reperfusion
Authors: Madonna R , Guarnieri SG , Kovacshazi CK , Gorbe AG , Giricz ZG , Geng YJ , Mariggio MA , Ferdinandy PF , De Caterina RD
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Cardiac stromal cells (CSCs) contain a pool of cells with supportive and paracrine functions. Various types of mesenchymal stromal cells (MSCs) can influence CSCs in the cardiac niche through their paracrine activity. Ischemia/reperfusion (I/R) leads to cell death and reduction of the paracrine activity of CSCs. The forced coexpression of telomerase reverse transcriptase (TERT) and myocardin (MYOCD), known to potentiate anti-apoptotic, pro-survival and pro-angiogenic activities of MSCs isolated from the adipose tissue (AT-MSCs), may increase CSC survival, favoring their paracrine activities.

Aim

To investigate the hypothesis that CSCs feature improved resistance to simulated I/R (SI/R) and increased commitment toward the cardiovascular lineage when preconditioned with conditioned media (CM) or extracellular vesicles (EV) released from AT-MSCs overexpressing TERT and MYOCD (T/M AT-MSCs).

Methods and Results

Murine CSCs were isolated with the cardiosphere (CSps) isolation technique.

T/M AT-MSCs and their secretome improved spontaneous intracellular calcium changes (Figure 1) and ryanodine receptor expression in aged CSps. The cytoprotective effect of AT-MSCs was tested in CSCs subjected to SI/R. SI/R induced cell death as compared to normoxia (28±4 vs 10±3%, p=0.02). Pretreatment with CM (15±2, p=0.02) or with the EV-enriched fraction (10±1%, p=0.02) obtained from mock-transduced AT-MSCs in normoxia reduced cell death after SI/R. The effect was more prononunced with CM (7±1%, p=0.01) or the EV-enriched fraction (2±1%, p=0.01) obtained from T/M AT-MSCs subjected to SI/R. In parallel, we observed lower expression of the apoptosis marker cleaved caspase-3 and higher expression of cardiac and vascular markers eNOS, sarcomeric α-actinin and cardiac actin.

Conclusions

The T/M AT-MSCs secretome exerts a cytoprotective effect and promotes development of CSCs undergoing SI/R towards a cardiovascular phenotype.
The role of tachycardia and beta-adrenergic stimulation in inducing early cardiac remodelling
Authors: Kiessling M , Djalinac N , Matzer I , Voglhuber J , Ljubojevic-Holzer S
Published: June 2022

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): BioTechMed Graz

Objective

Cardiac remodelling encompasses changes at the molecular, cellular and gene expression level following pathologic insult to the heart. Initially, it maintains cardiovascular homeostasis and allows patients to remain asymptomatic, but if untreated, it eventually progresses to symptomatic heart failure. Excessive β-adrenergic stimulation and tachycardia are potent triggers of cardiac remodelling; however, the underlying mechanisms of their cellular effects are not fully understood. Using neonatal rat ventricular cardiac myocytes (NRVCMs), we studied individual and synergistic potency of ß-adrenergic stimulation and tachycardia to modulate pathological gene expression profiles, as well as the effectiveness of ß-blockers (BB) in preventing these alterations.

Methods

Primary NRVCMs were isolated from 1-day-old neonatal Wistar rats, cultured for 3 days and subsequently stimulated for 3h at basal (1Hz) and tachycardia (8Hz) conditions either in (1) cell culture medium to determine the sole effect of tachycardia, (2) cell culture medium supplemented with ß-adrenergic agonist isoprenaline (ISO; 10µM) to investigate the influence of ß-adrenergic stimulation and signalling or (3) cell culture medium supplemented with ISO following 1h preincubation with propranolol (ISO+BB; 1µM) to assess the potential of BB in preventing gene reprogramming. Screening of relative mRNA levels of hypertrophic marker genes and regulators of ion homeostasis in cardiomyocytes was performed by qPCR and calculated using the 2-ΔΔCt quantification method.

Results

qPCR screening of the known hypertrophic marker genes revealed that tachycardia caused significant transcriptional upregulation of regulator of calcineurin 1 (RCAN1) and interleukin-6 receptor (IL6R). Treatment with ISO additionally upregulated RCAN1, while preincubation with BB resulted in a return towards baseline expression of both genes, completely blocking the effects of tachycardia alone or when combined with ISO stimulation. Interestingly, two potassium channel genes, KCNH2 and KCNJ2, responsible for expression of hERG and Kir2.1 channels, respectively, were unchanged with tachycardia alone but significantly downregulated upon additional stimulation with ISO. Preincubation with BB could - at least partially - reverse the effect.

Conclusion

In conclusion, we could show that apart from the well-documented effect of excessive ß-adrenergic stimulation on hypertrophic signalling in cardiomyocytes, it also has a direct, non-tachypacing mediated effect on the expression levels of hERG and Kir2.1 potassium channels, which may be causally involved in inducing early cardiac remodelling. Thus, a previously unidentified benefit of BB therapy may be restoring potassium homeostasis contributing to the prevention of adverse cardiac remodelling and its progression to heart failure.
Propafenone as potential AgoKir: exploration of long-term effects and mechanisms of propafenone on Kir2.1 channel
Authors: Li E , Kool W , Woolschot L , Van Der Heyden MAG
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Chinese Scholarship Council

Background

Inward rectifying potassium (Kir) channel expression and activity are tightly regulated within the heart. Kir channels play key roles in shaping cardiac action potentials, having a reduced conductance at depolarized potentials but contributing to the final stage of repolarization and resting membrane stability. The Kir2.1 channel protein has polyamine binding residues in both the transmembrane (D172) and the cytoplasmic domains (E224,E299), responsible for the process of inward rectification. A reduced functioning of Kir2.1 causes 1) Andersen-Tawil Syndrom and 2) is present in a subset of heart failure patients. Restoration of normal Kir2.1 function by agonists of Kir2.1 (AgoKirs) would be beneficial. The drug propafenone is identified as an AgoKir, but its long-term effects on Kir2.1 protein expression and subcellular localisation is unknown.

Purpose

To investigate propafenone's long-term effect on Kir2.1 expression and its underlying mechanisms in cell systems.

Methods

GFP, Dendra2 or non-tagged wildtype (WT) and mutant Kir2.1 expression constructs were transiently or stably (HEK-KWGF; CHO-KD cell lines) expressed in Human Embryonic Kidney and Chinese Hamster Ovary cells. Kir2.1 carried currents were measured by single cell patch clamp electrophysiology. Kir2.1 proteins expression levels were determined by Western blot analysis, whereas conventional immunofluorescence and advanced live-imaging microscopy were used to assess the subcellular localisation of Kir2.1 proteins. Propafenone was dissolved in DMSO,BaCl2 was used as Kir2.1 channel inhibitor.

Results

Acute administration of 0.1 and 0.5 µM propafenone increased Kir2.1 carried outward current confirming the drug's Agokir status. Propafenone dose-dependently increased WT Kir2.1 expression levels (2.63±0.40 fold increase at 25 µM and 2.75±0.56 fold increase at 50 µM, 24h) in a process that is independent of the E224, E299 and D172 polyamine binding sites, and the R312 residue which is adjacent to the proposed propafenone binding site. Propafenone (25, 50 µM, 24h) induced intracellular accumulation of WT and mutant Kir2.1 proteins in the late endosome/lysosome compartment (Figure). Channel inhibition by BaCl2 did not affect the propafenone responses on Kir2.1 expression levels or subcellular localisation.

Conclusion

Acute administration of propafenone at low concentrations increases Kir2.1 currents. Chronic propafenone treatment at only 25-100 times higher concentrations results in increased Kir2.1 protein expression levels and intracellular accumulation in late endosomes and/or lysosomes. Our data support the ability of propafenone at low concentrations to function as AgoKirs without disturbing Kir2.1 protein handing.
Functional remodeling of the mitochondrial Ca2+ uniporter complex in metabolic cardiomyopathy
Authors: Panel M , Fossier L , Lacote M , Azria L , Notarnicola C , Sicard P , Thireau J , Meli AC , Lacampagne A , Fauconnier J
Published: June 2022

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): Fondation pour la Recherche Médicale

ANR

Background

Calcium (Ca2+) uptake through the mitochondrial Ca2+ uniporter complex (MCUC) controls keys steps of the oxidative metabolism. In metabolic cardiomyopathy, myocardial mitochondrial Ca2+ uptake is impaired, but whether it is an early feature of the pathology remain unsolved.

Purpose

To establish whether mitochondrial Ca2+ dynamics and MCUC structure and function are affected at the early stage of the metabolic cardiomyopathy.

Methods and Results

Mice fed two weeks with a high fat sucrose diet display early features of metabolic disorders and diastolic dysfunction. Concomitantly, mitochondrial Ca2+-dependent pyruvate dehydrogenase activity and the beat-to-beat mitochondrial Ca2+ uptake are reduced. The impaired mitochondrial Ca2+ uptake was further confirmed by single channel recordings of the native MCUC incorporated in planar lipid bilayer demonstrating a reduction of the ion conductance and the open probability. The MCUC biochemical analysis showed an elevation of the EMRE subunit expression and an increase interaction of EMRE with the MICU1 subunits. Co-immunoprecipitation also revealed a deceased interaction of the pore forming subunits MCU with EMRE-MICU1 subcomplex. The displacement of the MCUC assembly was confirmed by the decrease in m-AAA protease-interacting protein 1 expression as well as its loss of binding with EMRE.

Conclusions

The remodeling of the MCUC integrity impacts mitochondrial Ca2+ homeostasis at the early stage of the metabolic cardiomyopathy and provides a novel post-translational paradigm of the MCUC regulation in pathophysiological context.
Hypoxic preconditioning effects change in hypertrophied or insulin resistant rat hearts
Authors: Babicheva V , Kozlovska M , Vasylenko M , Portnychenko A
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public Institution(s). Main funding source(s): Ministry of Education and Science of Ukraine

Purpose

Cardioprotective mechanisms in the hypertrophied or insulin resistant heart is not fully elucidated. Insulin like growth factor IGF-1 through downstream kinases PI3K/Akt/GSK3beta is known to exert cardioprotective effects and regulate myocardial remodeling, glucose metabolism, cell survival, apoptosis, oxidative stress etc. The aim was to characterize IGF-1/PI3K/Akt-mediated cardioprotection in hypertrophied or insulin resistant hearts after hypoxic preconditioning in response to severe whole body hypoxia or isolated heart ischemia/reperfusion.

Methods

Experiments were performed in male adult Wistar rats, and SHR with long-term heart hypertrophy. Insulin resistance (IR) was induced by high fat diet (58% kcal from fat). The animals were exposed to hypoxic preconditioning using mild hypobaric hypoxia séances in barochamber (5600 m, 3 h). In 24 h, hearts were isolated with urethane narcosis and subjected to ischemia/reperfusion in a Langendorff mode, infarct size was detected with TTC staining. The other group of rats after preconditioning were subjected to severe hypoxia (9000 m, 3 h). Inhibitor of PI3K wortmannin or blocker of IGF-1R picropodophyllin were used for testing of cytoprotective signalling. Protein expression were examined using Western blotting.

Results

In SHR, the myocardial expression of IGF-1 and Akt was lower by 42% or 63%, respectively, compared to Wistar. IR increased GSK-3beta expression and phosphorylation. Hypoxic preconditioning intensified IGF-1/PI3K/Akt-mediated cardioprotection, less pronounced in hypertrophied or insulin resistant hearts. Blockade of PI3K or IGF-1Rdecreased Akt phosphorylation, and abolished cytoprotective effects of preconditioning in view of mortality caused severe hypoxia, or of infarct size and cardiac function recovery in postischemic reperfusion. In SHR, hypoxia-induced cardioprotective effects and influences of the blockers were significantly reduced.

Conclusions

The long-term left ventricular hypertrophy is accompanied with reduction of IGF-1/IGF-1R/PI3K/Akt-dependent prohypertrophic and cardioprotective signalling. Hypoxic preconditioning mediated by IGF-1/PI3K/Akt-signalling loses its effectiveness during prolonged cardiac hypertrophy, as well as insulin resistance development.
Autopsy and genetic characterization of juvenile sudden cardiac arrest and death: the ToRSADE experience
Authors: Spinelli V , Girolami F , Maurizi N , Grifoni R , Maio V , Focardi M , Albora G , Nesi G , Coppini R , Cerbai E , Olivotto I
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public Institution(s). Main funding source(s): FAS-Salute 2014, regione Toscana

Background

Sudden cardiac arrest (SCA) or death (SCD) in young people represents a dramatic event, often leading to severe neurologic outcomes or death. However, the incidence of this phenomenon remains largely unknown, since the recording of cases, and consequently the identification of the underlying causes, requires a multi-professional and disciplinary approach, including genetic counselling.

Purpose

In this study, we aimed to monitor and investigate SCA and SCD in young people (≤50 years) recorded in the ToRSADE© registry comparing clinical and molecular data.

Methods and Results

A total of 22 blood samples were analyzed; 14 were collected from dead patients during autopsy and 8 from resuscitated patients after cardiac arrest. Next Generation Sequencing (NGS) analysis revealed 38% of total cases with Likely Pathogenetic (LP) variants associated to Cardiomyopathy (CM) or Channelopathy, and 61% with Variant of Uncertain Significance (VUS). In three cases, NGS confirmed autopsy and histology findings: the p.(Leu466Phe) variant in SCN5A associated with Brugada Syndrome (1a), the p.(Glu173del) in TNNT2 for Hypertrophic CM (1b) and the p. (Asn480Lysfs*20) in PKP2 for Arrhythmogenic Cardiomyopathy (AC) (1c).

Conclusions

Creation of the ToRSADE© registry allowed implementation of a blood repository for molecular and genetic analysis. Genetic analysis combined with clinical information and post-mortem evaluation constitute a multi-disciplinary approach to juvenile SCD and SCA, while providing medical and genetic assistance to families, public awareness especially among youths and athletes, as well as up-to-date research on the underlying mechanisms of cardiomyopathies.
Exogenous Growth Differentiation Factor 15 (GDF15) exerts direct cardioprotective properties towards myocardial ischemia reperfusion injury
Authors: Dogon G , Rigal ER , Rochette LR , Bejot YB , Vergely CV
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agence National de la Recherche (ANR)

Introduction

Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine which can be produced under certain pathological situations, mainly related to inflammatory stress, aging and disease. While clinical data suggest that GDF15 is a powerful risk factor in several high cardiovascular risks situations such as myocardial infarction and coronary artery disease, experimental studies rather consider this cytokine as a cardioprotective molecule.

Objective

We therefore aimed to clarify the direct cardiac effects of GDF15 during ischemia-reperfusion (I-R) injury, at concentrations found in patients with high cardiovascular risk, such as these of patients presenting with acute myocardial infarction or stroke.

Method

In vivo ischemia reperfusion: Wistar male rats (200-340 g) were anesthetized with isoflurane and intubated before a left thoracotomy was performed between the 3rd and the 4th intercostal space. Rats were injected with either saline (Control groups) or 2.5 µg/kg of GDF15 (GDF15 groups), 20 minutes before the transient ligation of the left anterior descending artery for 30 min followed by 24h of reperfusion.

Ex vivo ischemia reperfusion: Wistar male rats (250-400 g) were anesthetized with isoflurane before their hearts were isolated and perfused in a Langendorff model. Hearts were perfused either with saline (Control groups) or 2,000 ng/L of GDF15 upstream the coronary bed (GDF15 groups) for 10 minutes, then subjected to either 20 or 30 minutes of global normothermic total ischemia, followed by 2 h of reperfusion.

Results

GDF15 decreased the infarct size in vivo (42.4 ± 6 % vs. 65.3 ± 4.5 %, p<0.01) as well as in ex vivo (45.6 ± 3.8 % vs. 60.8 ± 3.8 %, p<0.05). Moreover, in our ex vivo model, GDF15 induced a better recovery of most contractile parameters after ischemia (higher left ventricular developed pressure, better heart rate recovery, better recovery in left ventricular contractility and relaxation, p<0.05 for all parameters).

Conclusion

These results demonstrate for the first time that exogenous preischemic short-term administration of GDF15 decreased cardiac cell death in vivo and also ex vivo, a situation where inflammatory, endocrine and nervous systems are not interfering. These original results suggest that GDF15 exerts direct cardioprotective properties towards ischemia-reperfusion injury. The molecular mechanisms have now to be investigated.
Diurnal Variation in thrombolytic status in patients presenting with STEMI
Authors: Gue Y X , Farag M , Spinthakis N , Wellsted D , Gorog D
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Prior studies mainly in healthy volunteers and patients with stable coronary artery disease (CAD) indicate circadian variation in spontaneous fibrinolytic activity. This is predominantly attributable to changes plasminogen activator inhibitor-1 (PAI-1) levels peaking between midnight and 06:00 hr, with a nadir at 18:00 hr. Whether circadian variation in spontaneous fibrinolysis exists amongst patients with ST-elevation myocardial infarction (STEMI) is unknown.

Purpose

It was our aim to assess circadian variation in fibrinolytic status in the acute setting in patients presenting with STEMI.

Methods

A prospective, observational study was conducted in patients presenting with STEMI for primary percutaneous coronary intervention (PPCI). Blood was tested on arrival pre-PPCI, after aspirin and P2Y12 inhibitor administration, but before any anticoagulant or antithrombotic agent administration in the cardiac cath lab. Venous blood was assessed to determine endogenous fibrinolysis using the Global Thrombosis Test, which utilises non-anticoagulated blood to assess the formation of an occlusive thrombus under high shear and the time taken for spontaneous restart of flow as a measure of endogenous fibrinolysis (lysis time, LT).

Results

A total of 527 patients were included, aged 64±13 years and 78% were male. 304 (58%) patients presented within working hours (08:00-17:00) with peak presentation between 11:00-12:00 and trough between 03:00 to 05:00 hrs.

Lysis time was not related to time of presentation. Time of presentation was divided into 4 groups (A 00:00-05:59, B 06:00-11:59, C 12:00-17:59, D 18:00-23:59 hrs). There was no significant difference in LT between patients presenting at the 4 timepoints (median 1362s [interquartile range IQR 1077-1808] vs 1503s [1182-2056] vs 1440s [1164-1998] vs. 1420s [1125-1820], respectively, p=0.340). When comparing Group A to C, the LT was not significantly different (1362s [1077-1808] vs. 1440 [1164-1998], p=0.413). The presentation time of patients with impaired endogenous fibrinolysis (LT>3000 sec) did not differ significantly from patients with normal endogenous fibrinolysis. The hourly variation was similar in diabetics and non-diabetics, but the variation in lysis time appeared blunted in patients taking long term aspirin prior to presentation compared to non-aspirin takers.

Conclusion

In contrast to the known circadian variation in fibrinolysis in normal volunteers, and stable CAD, in our large cohort of STEMI patients, there appears to be no relationship between time of presentation/onset of STEMI and the effectiveness spontaneous fibrinolysis. This is reflected in our observation, supported by most contemporary studies, that peak time of STEMI presentation is during the late morning, and this does not relate to known circadian variation in fibrinolysis markers in CAD.
Long-term impact of postnatal overfeeding on cardio-metabolism risk and on sensitivity to ischemia-reperfusion injury in vivo
Authors: Rigal E , Josse MJ , Dogon GD , Porcherot IP , Rochette LR , Guenancia CG , Vergely CV
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Introduction

Nutritional disturbances during the postnatal period may be responsible for a predisposition, or "programming", to increased cardio-metabolic risk and to a progressive alteration of left ventricular contractility in adulthood. However, these data have mainly obtained in young male mice, but less is known for older animals.

Purpose

Our aim was to evaluate the impact of postnatal overfeeding (PNOF) on cardiac function, on cardiac sensitivity to ischemia-reperfusion (I-R) injury in vivo and on glucose metabolism in young (4 months), adult (6 months) and old (12 months) male mice.

Methods

PNOF was induced by the reduction of litter size of C57/BL6 mice immediately after birth: normally-fed group (NF) was composed of 9 male pups/mother and overfed group (OF) of 3 pups/mother. Echocardiography and blood sugar tests (glucose tolerance and insulin resistance) have been performed at all ages. An in vivo ischemia-reperfusion injury was induced by the ligation of the anterior interventricular artery for 45 minutes followed by 24 h of reperfusion. All experiments have been done on 4-, 6- and 12-months aged male mice.

Results

PNOF induced an early and permanent increase in body weight in OF group, independently of mice’s age (+23% at 24 days of life, +14% at 4 months, +23% at 6 and 12 months, compared to NF group). The echocardiographic measurements showed an alteration of contractile function from 6 months aged males and up to 12 months as evidenced by a decrease of the left ventricular ejection fraction (-11 % for OF males from 6 to 12 months, compared to NF groups). These cardiac alterations were associated with glucose metabolism imbalance: OF males presented glucose intolerance and insulin resistance from 4 to 12 months of age. To finish, PNOF induced a significant increase of infarct size at 4 months (+37%, p<0.01, n=8), 6 months (+32%, p<0.05, n=9) and 12 months (+38%, p<0,05, n=9) after cardiac surgery.

Conclusion

Nutritional programming through short-term PNOF induced an early alteration of glucose metabolism and was associated with a constant higher susceptibility to myocardial I-R injury in vivo. Moreover, mice which were submitted to PNOF developed altered cardiac contractility at 6 months and up to 12 months. The cellular and biochemical mechanism of these pathological modifications induced by PNOF need further exploration but could involve alterations in cardiomyocyte pathways, and/or modification of global inflammatory status.