Increased Wall Thickness Research Articles

A Dynamic Sheep Model to Induce Pulmonary Hypertension and Right Ventricular Failure.

Decompensated right ventricular failure (RVF) in pulmonary hypertension (PH) is fatal, with limited medical treatment options. Developing and testing novel therapeutics for PH requires a clinically relevant large animal model of increased pulmonary vascular resistance and RVF. This manuscript describes the method to induce an ovine PH-RVF model that utilizes left pulmonary artery (LPA) ligation, progressive main pulmonary artery (MPA) banding, and insertion of an RV pressure line for monitoring. The PA cuff and RV pressure tubing are connected to subcutaneous access ports. This model of PH-RVF is a versatile platform to control not only the disease severity, but also the RV's phenotypic response. Subjects undergo progressive PA band adjustments twice per week for approximately 9weeks with sequential measures of RV pressure, PA cuff pressures, and mixed venous blood gas (SvO2). Subjects can further be exercised on a livestock treadmill while hemodynamic parameters are captured. At the initiation and endpoint of this model, ventricular function and dimensions are assessed using echocardiography. In this model, RV mean and systolic pressure increased to 28±5 and 57±7mmHg at week 1, and further to 44±7 and 93±18mmHg by week 9, respectively. Echocardiography demonstrates characteristic findings of PH-RVF, notably RV dilation, increased wall thickness, and septal bowing. The rate of PA banding has a significant impact on SvO2 and thus the model can be titrated to elicit varying RV phenotypes. When the PA cuff is tightened rapidly, it can lead to a precipitous decline in SvO2, leading to RV decompensation, whereas a slower, more paced strategy leads to an adaptive RV stress-load response that maintains physiologic SvO2. A faster rate of PA banding will also lead to more severe liver fibrosis. The addition of controlled exercise provides a useful platform for assessing the effects of physical exertion in a PH-RVF model. This chronic PH-RVF model provides a valuable tool for studying molecular mechanisms, developing diagnostic biomarkers, and evaluating mechanical circulatory support systems.

Relationship between Pulmonary Gas Exchange Function and Brain Uptake Dynamics Investigated with Hyperpolarized 129Xe MR Imaging and Spectroscopy in a Murine Model of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a complex multisystem disease associated with comorbidities outside the lungs. The aim of this study was to measure changes in metrics of pulmonary gas exchange function and brain tissue metabolism in a mouse model of COPD using hyperpolarized 129Xe (HP 129Xe) MRI/MR spectroscopy (MRS) and investigate the relationship between the metrics of lung and brain. COPD phenotypes were induced in 15 mice by 6-week administration of cigarette smoke extract (CSE) and lipopolysaccharide (LPS). A separate negative control (NC) group was formed of 6 mice administered with saline for 6 weeks. After these 6-week administrations, the pulmonary gas exchange function parameter fD (%) and the rate constant, α (s-1), which are composed of the cerebral blood flow Fi and the longitudinal relaxation rate 1/T1i in brain tissue, were evaluated by HP 129Xe MRI/MRS. The fD of CSE-LPS mice was significantly lower than that of NC mice, which was in parallel with an increase in bronchial wall thickness. The α in the CSE-LPS mice decreased with the decrease of fD in contrast to the trend in the NC mice. To further elucidate the opposed trend, the contribution of T1i was separately determined by measuring Fi. The T1i in the CSE-LPS mice was found to correlate negatively with fD as opposed to the positive trend in the NC mice. The opposite trend in T1i between CSE-LPS and NC mice suggests hypoxia in the brain, which is induced by the impaired oxygen uptake as indicated by the reduced fD. This study demonstrates the feasibility of using HP 129Xe MRI/MRS to study pathological mechanisms of brain dysfunction in comorbidities with COPD.

Weight optimization of 200 mm diameter rocket motor tube using finite element method

The lightweight design of the rocket motor tube is a critical requirement for enhancing the rocket's flight performance. This study assesses the impact of wall thickness, cap thickness, and fillet radius on structural strength and the optimization of rocket motor tube weight using the finite element method with the assistance of Ansys software. A total of 12 finite element model variations, utilizing Aluminium 6061-T6, were developed and subjected to a uniform internal operating pressure load of 10 MPa. The design includes wall thickness variations of 8 and 10 mm, cap thickness options of 25 and 30 mm, and fillet radius dimensions of 20, 25, and 30 mm, allowing for a comprehensive comparison to achieve the required minimum safety factor while minimizing structural weight. The research concludes that increasing the fillet radius is a more recommended approach compared to increasing wall thickness and cap thickness. The results indicate that Model 9, with wall thickness, cap thickness, and fillet radius dimensions of 10 mm, 25 mm, and 30 mm, respectively, is the optimal choice due to its lightweight construction.

Research on casing damage mechanism and prevention and control under creep behavior of salt-gypsum layer

As a good cap rock, the salt-gypsum layer often contains abundant oil and gas resources, but it has strong plastic flow and creep properties, resulting in frequent casing damage problems. Therefore, a new method is proposed to prevent and control casing failure in creep formation by using solid expandable tubular (SET). Based on the Heard model, the creep behavior of formation was described. The expansion experiment of the SET, the material tensile experiment of casing and SET with different expansion rates were carried out. The three-dimensional mechanical model and finite element model of casing-cement sheath- (SET) -formation were established. Numerical simulation of creep behavior of salt-gypsum layer under non-uniform in-situ stress was carried out. Comparative study of casing damage mechanism in two cases with or without SET prevention and control. The influence of sensitive factors such as SET wall thickness and expansion rate on the failure behavior of casing prevented and controlled by SET were analyzed. The results show that (1) In the direction of the maximum horizontal in-situ stress, the stress on the outer surface of the casing is large. In the direction of the minimum horizontal in-situ stress, the stress on the inner surface of the casing is the largest, and the material yield failure occurs first at this position of the casing. The compression deformation of casing is greater than the tensile deformation. The casing is oval after deformation. (2) By increasing steel grade and wall thickness of casing, the service time of the casing under creep behavior of salt-gypsum layer can be prolonged. However, while increasing cost and reducing diameter, it has not played a role in preventing casing failure. (3) By using the method of SET prevention and control, the casing stress is more evenly distributed, the maximum stress is effectively reduced, the stress growth rate is slowed down, and the external collapse resistance ability is significantly enhanced. The maximum stress of the casing is reduced by up to 24.96 %. The larger the wall thickness of the SET, the better the prevention and control effect, and the longer the service time of the casing. The increase of the ultimate wall thickness of the SET with high expansion rate can effectively make up for its poor prevention and control effect. (4) The new method of adding the SET between salt-gypsum layer and cement sheath has the advantages of increasing casing inner diameter, optimizing wellbore structure, reducing cost and wellbore risk. The research results can provide some reference value for the prevention and control of casing failure in creep salt-gypsum layer.

Buoyancy influencing convective heat transfer characteristics of supercritical CO2 in a serpentine solar receiver tube at low Reynolds number

The tubular receiver is one of the most promising forms of supercritical CO2 (S-CO2) receiver. Due to the high-temperature and high-pressure working condition of S-CO2, the pressure resistance of solar receiver tube faces great challenges. The convective heat transfer performance of S-CO2 will be significantly improved by using the serpentine solar receiver tube instead of the traditional straight solar receiver tube in the S-CO2 tubular solar receiver, which will offset the negative effects of increased thermal resistance caused by increasing wall thickness to improve pressure resistance. Centrifugal buoyancy and gravitational buoyancy are important factors affecting the convective heat transfer characteristics of S-CO2 in serpentine tube which are numerically studied in this paper. The results show effect of buoyancy in the serpentine tube can significantly improve the convective heat transfer performance with a maximum value of 23% and reduce the entropy generation with a maximum value of 22% compared with straight tube. The convective heat transfer performance of S-CO2 for the downward flow is stronger than the upward flow due to the effect of gravitational buoyancy on the intensity of turbulence kinetic energy near the wall. The dominant position of centrifugal buoyancy and gravitational buoyancy affects the convective heat transfer characteristics of S-CO2 in serpentine tube. The synergistic/competitive relationship between centrifugal buoyancy and gravitational buoyancy will promote/suppress the change of the flow field which affects the convective heat transfer characteristics of S-CO2 in serpentine tube. The conclusions of this work can provide theoretical guidance for the design and optimization of tubular receiver using S-CO2 as heat transfer fluid.

Research on Material Selection Method and Brittle Fracture Mechanism of High-Pressure Pipeline

Aiming at the problem of the brittle fracture of pressure pipeline, the elastic constraint structure is described by using members and engineering building structures, and the concept of elastic constraint is proposed. Through the stress field analysis of the pressure pipeline under internal pressure, it is found that the pressure pipeline under internal pressure is an elastic constraint structure. The elastic constraint effect is applied to the pressure pipeline to explore the influence of elastic constraint effect on the brittle fracture of pressure pipeline. The critical wall thickness and limit load of different materials are calculated by the limit bearing formula. Through simulation analysis of materials with different yield ratios and pipelines with different wall thicknesses of the same material (yield ratio is the ratio of yield strength to tensile strength), it was found that pressure pipelines made of the same material have an increased load-bearing capacity as the wall thickness increases, but their own elastic constraint effects are becoming more obvious, and the probability of the brittle fracture of the pipeline is higher. When the wall thickness of pressure pipelines made of materials with different yield ratios is certain, the lower the yield ratio is, the more likely the pipeline is to generate plastic deformation and the larger the deformation capacity is; the higher the yield ratio, the poorer the plastic deformation capacity of the pipeline and the smaller the deformation capacity. Pipelines with large yield ratio are more sensitive to the brittle fracture than those with small yield ratio.

Interfacial nanolayer effect on thermophysical properties of silica-paraffin phase change material - A molecular dynamics simulation

Thermophysical properties of composite phase change materials (PCMs) are influenced by the interfacial nanolayer. Molecular dynamics (MD) method is used to study the effect of interfacial nanolayer on thermophysical properties of silica-paraffin composite PCM. The simulation results show that the melting enthalpy is reduced from 197.9 J·g−1 to 29.1 J·g−1, and the thermal conductivity is enhanced from 0.142 W·m−1·K−1 to 0.268 W·m−1·K−1, when the silica thickness is increased from 0 to 15.0 Å. The interfacial nanolayer is observed in composite PCM, and its thickness increases with the increase of silica wall thickness. In the composite PCM with 7.0 Å silica wall, a loss of 62.9% in the melting enthalpy is observed, with 32.6% attributed to the silica mass and 30.3% attributed to the nanolayer. Based on that, a modified model is proposed to predict the melting enthalpy of composite PCMs by considering the effects of both silica mass fraction and nanolayer. To reveal the thermal conductivity enhancement mechanism, the total heat flux is decomposed into three terms (namely, kinetic energy term, potential energy term and interaction energy term). It is found that the interaction energy term has the largest contribution to the total heat flux. The presence of nanolayer strengths the interactions, leading to the thermal conductivity enhancement.

Crashworthiness of Foam-Filled and Reinforced Honeycomb Crash Absorbers in Transverse Direction

AbstractHoneycomb crash absorbers have been widely studied as energy absorption devices for use in automotive industries. However, none of these investigations have studied the side impact of empty and foam-filled honeycomb absorbers and adding stiffeners between the different layers of the corrugated sheets which are composing the honeycomb structure to analyse the structure under transverse (L-direction) impacts. In this paper, the foam-filled and reinforced honeycomb crash absorbers are investigated under axial (T) and transverse (L) loading directions. Experimental results for both empty and foam-filled specimens under quasi-static and impact loads were implemented to validate the developed finite element model. Finite element analysis (FEA) was performed to find out the crashworthiness behaviour of the structure under axial and transverse impacts according to road conditions. Finally, a new design of stiffened honeycomb crash absorber was developed and investigated to reduce the level of acceleration experienced by the passengers during the crash event. In this regard, it is concluded that all the requirements related to the energy absorption capabilities and generated deceleration under impact loading can be met by introducing an advanced method to reinforce honeycomb absorbers using stiffeners. It is also proven that the thickness of these stiffeners will not significantly influence the force levels. Due to increase of wall thickness from 1 to 3 mm, the mean crushing force increased from 129 kN to 148 kN. This growth is not sufficient as the goal is to obtain a mean crushing force of 300 kN. Thickening the stiffeners would lead to a loss of efficiency of the structure, as the small increase in mean force would not make up for the gain in mass. Thus, increasing the corrugated sheet’ thickness becomes necessary.

Prevalence of Gallbladder Malignancy in Gallstone Diseases

Background & objective: Carcinoma (Ca) of the gallbladder is a rare disease. But its prognosis is poor. Early diagnosis of Ca gallbladder, though important, is rarely achieved due to lack of symptoms and physical signs. However, it is frequently associated with gallstone diseases. It is, therefore, of utmost importance to do a routine histopathological examination of all gallbladder specimens after cholecystectomy is done for gallstone diseases. The present study was undertaken to find the prevalence of Ca gallbladder in gallstone diseases. Methods: This descriptive study was conducted in the Department of Surgery, BSMMU Hospital, and in the Public Medical College Hospitals of Dhaka over a period of eight months from July 2011 to February 2012. A total of 1012specimens of gallbladder were taken from the patients who underwent either laparoscopic or open cholecystectomy for gallstone diseases in the above-mentioned hospitals during the study period. Following the operation, the resected specimens or the biopsies taken from the gallbladder were collected in 10% formaldehyde solution and were sent to the Histopathology Departments of the respective hospitals, for confirmation of diagnoses as well as for histological grading and typing. Result: Of the 1012 cases of operated gallbladder for cholelithiasis, 28(2.7%) cases were histopathologically diagnosed as having Ca gallbladder. The age incidence of Ca gallbladder varied from 43 – 71 years. The highest incidence was observed in the 6th decade (53.6%) followed by the 5th decade of life (28.5%). Out of 28 cases of Ca gallbladder, 15(53.6%) exhibited increased wall thickness. All 28 cases were adenocarcinoma; of them, 25(89.3%) were poorly differentiated and 3(10.7%) were well-differentiated carcinoma. Non-squamous cell carcinoma or other variants were found. The majority (82.1%) of the cases was of infiltrative scirrhous (a hard slow-growing malignant tumor having a preponderance of fibrous tissue) type and the rest (17.9%) fungating type. Staging of the disease stratified 4(14.3%) cases as Stage-IV, 3(10.7%) cases as Stage-Ill, 8(28.6%) cases as Stage-II, and 13(46.4%) cases of Stage-I. Conclusion: The study concluded that the prevalence of malignancy in gallstone disease is rare. The incidence is highest in the 6th decade of life and females are more often affected than males. As older people with gallstone diseases are at increased risk of having gallbladder malignancy, it is imperative that older patients with gallstone diseases should be routinely examined for evidence of carcinoma. Ibrahim Card Med J 2022; 12 (2): 59-63

Structure design of porous TC4 alloy with excellent mechanical properties prepared by laser-powder bed fusion

Porous Ti6Al4V (TC4) alloy with a hexagonal structure (optimized side lengths of 700 μm and wall thickness ranging from 100 to 300 μm) was designed by finite element method (FEM) and prepared by laser-powder bed fusion (L-PBF) to improve mechanical compatibility. The porous TC4 alloys were composed of α′-Ti and a little β-Ti phases. The increasing wall thickness of the porous TC4 alloy induced the decrease in effective average diameter of grain from 1.97 to about 1.28 μm and the increase of average density of geometrically necessary dislocation (GND) from 4.46 × 1014 to 6.07 × 1014 m2. When the wall thickness was equal to or greater than 200 μm, the porous TC4 alloy exhibited high yield strength (about 550 MPa) and a proper elastic modulus of (14.4–15.4 GPa). This study could provide a reference for the material design of a new porous TC4 alloy with excellent mechanical properties.

Effect of bladder volume and compliance on ultrasonographic measurement of bladder wall thickness in children with neurogenic bladder dysfunction

Spina bifida is the most common cause of neurogenic bladder dysfunction in children. Measurement of bladder wall thickness (BWT) is non-invasive, low-cost, and may be complementary to urodynamics in demonstrating bladder condition. It is still unknown the wall thickness response to volume change in bladders with different compliance states. To determine the most appropriate measurement technique by revealing the differences in measurements performed in different compliance and volume conditions in children with neurogenic bladder. In the prospective study in 2022, patients with spina bifida who continued their urological follow-up in our spina bifida center were included. Patients with a diagnosis of the neurogenic bladder who performed clean intermittent catheterization at least 4-6 times a day and had a recent urodynamic result in the last 6 months were included in the study. According to urodynamic results, patients were divided into two groups normocompliant (NC) and low-compliant (LC) bladders. BWT measurements were made from the anterior, posterior, right lateral, and left lateral walls of the bladder 3 times as full, half-volume, and an empty bladder. The study included 50 patients (NC group n:21, LC group n:29). The mean age of 24 female and 26 male patients was 6.45±4.07 years. In all BWT measurements, a significant increase in wall thickness was observed with decreasing bladder volume. The best correlation between bladder volume and BWT was found in the anterior wall with a weak negative correlation (p=0.049, r=-0.280). However, lateral wall measurements were significantly higher in low compliant patients compared to normocompliant patients when the bladder was full. The mean right lateral wall thickness was 1.58±0.68mm in the NC group and 2.18±1.35mm in the LC group (p=0.044). Left lateral wall thickness was 1.45±0.44mm in the NC group and 2.02±1.4mm in the LC group (p=0.033). Although standardization has been tried to be achieved in BWT measurements, we understand from the studies in the literature that there is no unity in practice. Lateral wall measurements were found to be significantly higher in LC patients compared to normocompliants in full bladder suggesting that more accurate BWT follow-up can be performed with lateral wall measurements in neurogenic bladder patients if bladder compliance is low. The present study seems to be the first study in the literature in which bladder compliance and ultrasonographic bladder wall thickness measurements were evaluated together in children with neurogenic bladder dysfunction.

Ultrastructural Architecture Studies of Pancreas in Guinea pig

Background: The pancreas is an accessory organ of the digestive system and also an important endocrine organ of vertebrates that produce and release substances in the body. The pancreas has both endocrine and exocrine function. Its endocrine function is to regulate blood sugar levels by secretion of hormones like insulin, glucagon, stomatostatin and pancreatic polypeptide and an exocrine function that helps in digestion. The study was performed to document the ultrastructural details of pancreas of guinea pigs by scanning and transmission electron microscopy. Methods: Six adult healthy guinea pigs of 16-32 weeks of age (Irrespective of sex) were procured from the Department of Laboratory Animal Medicine, TANUVAS as per ethical committee approval. Animals were dissected according to standard operating procedure by using the Carbon dioxide asphyxiations as per CPCSEA norms and pancreatic pieces were utilised for SEM and TEM study. Result: Pancreas was irregular in shaped and showed splenic, ventricular and intestinal lobes. In SEM, the parenchyma was covered by the dense irregular capsule. Each lobule contained many acini which were connected by a thin, long duct with branched pattern arrangement with increasing wall thickness and diameter. In TEM, the pancreatic tissue consisted of glandular lobules comprised of acini, islets of Langerhans and connective tissue between the lobules. Numerous mitochondria and golgi complexes were also present in the acinar cell cytoplasm along with zymogen granules and rough endoplasmic reticulum. The centroacinar cells were also found. A special type of interstitial cell named telocytes and each was found with many telopodes in the exocrine part of pancreatic parenchyma. Among the four islet cell types, alpha and beta cells could be identified.

Rare Association of Takayasu Arteritis and Antiphospholipid Syndrome with Severe Thrombocytopenia

The association of Takayasu arteritis (TA) with antiphospholipid syndrome (APS) has rarely been described in the literature. This paper reports the first documented case of TA and APS in a 24-year-old woman in Bangladesh. This patient had claudication pain in upper and lower limbs for four years and Raynaud’s phenomenon in right hand for eight months. During the course of her illness, she suddenly developed deep vein thrombosis in left superficial femoral, popliteal and posterior tibial veins. Conventional angiography revealed total occlusion of right subclavian artery and 60-70% stenosis of right common iliac artery. CT angiography of right upper limb also supported these findings along with increased wall thickening in the 2nd part of right subclavian artery and moderate narrowing of the 1st part of right axillary artery. She had persistently positive anticardiolipin antibodies in high titers, positive lupus anticoagulant (LA), prolonged activated partial thromboplastin time (APTT) and severe thrombocytopenia. We started high dose prednisolone (1mg/kg daily). Her platelet count increased rapidly. Based on review of 10 case reports, we considered the rare association of TA and APS. Both conditions should be determined promptly for the sake of early institution of the appropriate therapy. Bangabandhu Sheikh Mujib Med. Coll. J. 2023;2(1): 59-63

The role of charme in the phenotype and function of resident cardiac mesenchymal stromal cells

Abstract Background Charme is a murine long non-coding RNA with specific expression in striated muscles, presenting a human orthologue with 45% identity. Its depletion leads to incomplete muscle differentiation. Charme-/- mice display an altered cardiac phenotype with increased wall thickness and reduced chamber dimensions due to myocyte hyperplasia. Left ventricular dilatation and reduced fractional shortening are detected in aged Charme-/- mice. Embryonic myocardial architecture reveals aberrant compaction and ventricular hypotrabeculation, resembling some congenital cardiomyopathies. Cardiac mesenchymal stromal cells (CMSCs) play key roles in tissue homeostasis and pathophysiology, by maintaining the extracellular matrix and by paracrine action on all myocardial cells. Purpose To elucidate the phenotype, paracrine function, and myofibroblast differentiation capacity of resident CMSCs in the Charme-/- mouse model. Methods CMSCs were isolated from 5-week-old wild-type (WT) and Charme-/- mice by explant culture, pooling at least 4 different hearts per culture. Results Charme-/- CMSCs showed increased features of primitive phenotypes, such as enhanced spontaneous spheroid growth (123,6±11,9 vs 51,0±6,4 spheroids/well; N=8, p<0,0001) and clonogenesis efficiency (2,7±0,5-fold; N=7, p<0,05) compared to WT cells. Charme-/- CMSCs also showed increased migration ability (Charme-/-: 68,5±2,7% vs WT: 80,2±0,7% wound area; N=2). Flow cytometry identified a reduced proportion of lin-/Sca1+/CD90+ primitive mesenchymal cells in Charme-/- versus WT CMSCs (7,4±1,6% vs 56,9±6,5%; N=6, p<0,05). Western blot analysis on Charme-/- whole cardiac tissue showed reduced collagen I and collagen I/III protein ratio compared to WT hearts (0,17±0,03 vs 0,85±0,10 normalized OD; N=4, p<0,005). Stimulation with TGFb-1 resulted in lower expression of fibroblast activation markers compared to WT CMSCs, as assessed by immunofluorescence staining for aSMA (0,49±0,05 vs 0,76±0,10 mean fluorescence intensity; N=6-12, p<0,05) and collagen I/III mRNA expression ratio (1,3±0,1 vs 2,2±0,4 2^-DCt; N=3, p<0,01). The secretome of Charme-/- CMSCs revealed a general depletion in many cardioprotective cytokines, included in the KEGG term "PI3K-Akt signalling pathway" (FDR<0,0005) and classified in Gene Ontology categories of myoblast differentiation and fusion (GO:1901739, GO:1901741, GO:0045663, GO:0045661; FDR<0,05). In line with this, the secretome of TGFb1-stimulated Charme-/- CMSCs was less effective in sustaining cardiomyocyte survival versus the WT CMSC secretome (1,70±0,03 vs 1,90±0,04 normalized OD at 48h; N=5, p<0,005). Conclusions Charme-/- CMSCs show a less mature phenotype associated to reduced collagen I presence in situ, reduced activation and differentiation upon stimulation, and impaired cardioprotective paracrine functions, suggesting a key role of Charme in the physiology of the cardiac stroma, possibly mediating in part the altered cardiac phenotype of Charme-/- mice.

Rimeporide, a first in class Na/H exchanger-1 inhibitor, ameliorates right ventricular dysfunction and pulmonary arterial hypertension in a SuHx model

Abstract Background Pulmonary arterial hypertension (PAH) is characterized by pulmonary vasoconstriction and vascular remodeling leading to right ventricular (RV) failure. Although RV function is the major prognostic factor in PAH, no RV-specific therapies exist. The Na+/H+ exchanger type 1 (NHE1) regulates the intra- and extracellular pH balance mainly through the 1:1 exchange of intracellular H+ with extracellular Na+. Increased NHE-1 activity is involved in several diseases, including hypoxic PAH. Inhibition of NHE-1 activity attenuates pulmonary vascular remodeling in rodents exposed to hypoxia but its potential direct contribution in RV remodeling remains unclear. Aim In the current study, we aimed to investigate the effect of NHE-1 inhibition by Rimeporide a preclinical hypoxic models of PH: Sugen5416/hypoxia. Methods Sugen/hypoxia model: PAH was induced in adult Sprague-Dawley rats with a single injection of SU5416 (20 mg/kg) followed by 3 weeks of hypoxia (10% O2; Sugen/Hypoxia model: SuHx) and then return to normoxia. Control rats were injected with equal volume of vehicle. At week 5 post-injection, control and SuHx rats were treated with rimeporide (100 mg/Kg daily in drinking water, n=10/group) or placebo (n=11/group) for 3 weeks. Echocardiography and blood sampling were performed. RV phenotype was monitored by echocardiography and hemodynamic analysis. Lung and heart were collected for histological and protein expression analysis, such as NHE-1 (target of Rimeporide). Results SuHx caused severe PAH and RV dysfunction. RV dysfunction was accompanied by an increase in RV hypertrophy and RV fibrosis and PA remodeling (increase in the arteriolar wall thickness and fibrosis). A marked increase in macrophages was found in lung and RV tissues but not in LV. Moreover, Western blot analysis showed that RV protein levels of NHE-1 was higher in SuHx rats than Normoxia rats. Treatment with Rimeporide reversed SuHx-induced PAH as well as RV dysfunction and blunted pulmonary and RV inflammation, RV NHE-1 protein expression. Conclusion Our results indicate that NHE-1 levels are increased in RV tissues from SuHx-induced PAH rats. Rimeporide, through NHE-1 inhibition, might be a potential new target for treatment of RV dysfunction and PAH.

The electrophysiological substrate of biopsy-proven cardiac amyloidosis

Abstract Background Cardiac amyloidoses (CA) are an increasingly recognized group of infiltrative cardiomyopathies associated with high risk of major adverse cardiac events. Endomyocardial biopsy (EMB) may be required to differentiate the amyloid type (mainly, Immunoglobulin light chain [AL] versus transthyretin-related [ATTR]) in some cases. Purpose The aim of this study was to provide the first description of the right ventricular (RV) electroanatomical substrate of CA, and assess its association with EMB findings and clinical outcomes. Methods We enrolled ten consecutive patients undergoing EMB for suspected CA (median age, 68[63-77]; male, 50%) in a monocentric, observational, retrospective study. All patients had a clinical diagnosis of CA, but a diagnosis of CA type was hampered by the presence of inconclusive or discordant laboratory-imaging findings (abnormal serum free light chain assay and positive bone scintigraphy, n=5; ambiguous imaging results, n=4; abnormal serum free light chain assay and TTR gene mutation, n=1). Therefore, each patient underwent RV high-density electroanatomical voltage mapping (EVM) and EMB. The primary outcome was death or hospitalization at 1-year follow-up. We recorded electrogram features at EMB sampling sites and in the overall RV, and explored their correlations with histopathological findings and primary outcomes events. Results A final EMB-proven diagnosis of AL or ATTR CA was formulated in 6 and 4 patients, respectively. Electrogram amplitudes in the bipolar and unipolar configurations averaged 1.58±0.65 mV, and 5.38±1.41 in the overall RV. We found a significant inverse correlation between unipolar electrogram amplitude and amyloid burden at EMB (p<0.001); the unipolar voltage cutoff that best identified regions with >15% amyloid tissue infiltration according to Youden index was 9.1 mV (sensitivity, 43%; specificity, 100%; accuracy, 77%). At 1-year follow-up, 6 patients (60%) experienced a primary outcome event. Compared to subjects with uneventful follow-up, patients with a primary outcome event had larger unipolar low-voltage zones (32.3 [6.1] cm2 vs. 20.7 [6.5] cm2, p=0.043) and bipolar dense scar areas (6.1 [2.3] cm2 vs. 1.8 [0.7] cm2, p=0.005), and after pooling mapping points from all patients, unipolar electrogram amplitude was moderately associated with primary outcome events (AUC: 0.65 [95% CI, 0.64-0.65]). Conclusions In CA, electrogram amplitudes are around the lower limit of normal, yet disproportionately low compared to the increased wall thickness. We found evidence that unipolar electrogram amplitude may be a quantitative marker of amyloid burden, possibly associated with adverse clinical outcomes.EVM and EMB in ATTR cardiac amyloidosisEVM and EMB in AL cardiac amyloidosis

Development of KER-012, a modified ActRIIB ligand trap, for the treatment of pulmonary arterial hypertension

Abstract Background Pulmonary Arterial Hypertension (PAH) is a debilitating disorder characterized by elevated pulmonary vascular resistance (PVR) due to severe constriction obliteration of pulmonary vessels (Tielemans 2019). The pathology of PAH is driven by endothelial dysfunction and vascular remodeling that leads to increased wall thickening and resistance to blood flow. Dysregulated TGF-β, specifically SMAD signaling, is a key molecular defect in proliferative thickening of pulmonary arterioles in PAH leading to increased arterial pressure and compensatory right ventricular hypertrophy, ultimately resulting in decompensated right heart failure. Increased levels of activin A, a TGF-β superfamily ligand, have been found in PAH patients, and in the lungs of hypoxia-induced pulmonary hypertensive mice (Yndestad 2009). KER-012 is an investigational modified ActRIIB ligand trap designed to bind and inhibit activin A, activin B, GDF8 and GDF11 to maximally inhibit SMAD2/3 (pro proliferative), while permitting SMAD1/5/9 (anti-proliferative) signaling. This profile is expected to rebalance defective SMAD signaling in PAH and potentially delay or reverse disease progression. Aim To evaluate safety and tolerability of KER-012 in healthy post-menopausal women (PMW) and present the planned design of a Phase 2 trial in participants with PAH. Methods A two-part Phase 1 study has been conducted with KER-012 in healthy PMW. Participants received either placebo or a single dose of KER-012 ranging between 0.75 and 5.0 mg/kg in Part 1 or multiple doses between 0.75 and 4.5 mg/kg in Part 2 subcutaneously once every 4 weeks over a 12-week period. Safety, PK and biomarkers of activin target engagement were assessed. Results KER-012 was generally well tolerated at dose levels up to 5 mg/kg as a single dose and at dose levels up to 4.5 mg/kg administered Q4W for a total of 3 doses (Table 1). Maximal target engagement of KER-012, as demonstrated by changes in biomarkers of activin inhibition, namely follicle stimulating hormone (FSH) and bone specific alkaline phosphatase (BSAP), was observed in this study. As previous studies with activin receptor type II ligand traps have shown a potentially dose-limiting increase in erythropoiesis, changes in red blood cells (RBC) were closely monitored in this study. KER-012 did not elicit any changes in hemoglobin or RBC count in the Phase 1 study (Figure 1). Summary KER-012 was generally well tolerated in healthy participants. The observed biomarker changes are consistent with inhibition of activins, suggestive of a balance shift in favor of signaling via the anti-proliferative SMAD 1/5/9 pathway. Based on this mechanism, administration of KER-012 could potentially result in reverse vascular remodeling and clinical cardiopulmonary improvements in patients with PAH, without targeting erythropoietic pathways. Given this profile, KER-012 is being advanced for development in patients with PAH in an upcoming Ph2 clinical trial (Figure 2).

Influence of Perivascular Adipose Tissue on Microcirculation: A Link Between Hypertension and Obesity.

Alterations in microcirculation play a crucial role in the pathogenesis of cardiovascular and metabolic disorders such as obesity and hypertension. The small resistance arteries of these patients show a typical remodeling, as indicated by an increase of media or total wall thickness to lumen diameter ratio that impairs organ flow reserve. The majority of blood vessels are surrounded by a fat depot which is termed perivascular adipose tissue (PVAT). In recent years, data from several studies have indicated that PVAT is an endocrine organ that can produce a variety of adipokines and cytokines, which may participate in the regulation of vascular tone, and the secretory profile varies with adipocyte phenotype and disease status. The PVAT of lean humans largely secretes the vasodilator adiponectin, which will act in a paracrine fashion to reduce peripheral resistance and improve nutrient uptake into tissues, thereby protecting against the development of hypertension and diabetes. In obesity, PVAT becomes enlarged and inflamed, and the bioavailability of adiponectin is reduced. The inevitable consequence is a rise in peripheral resistance with higher blood pressure. The interrelationship between obesity and hypertension could be explained, at least in part, by a cross-talk between microcirculation and PVAT. In this article, we propose an integrated pathophysiological approach of this relationship, in order to better clarify its role in obesity and hypertension, as the basis for effective and specific prevention and treatment.

Abstract 19092: Endothelial Caveolin-1 Deficiency Increases Susceptibility to Lethal Heart Failure in Male Mice With Hypoxia-Induced Pulmonary Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is an incurable disease with high mortality. Reduced endothelial cell caveolin-1 (EC Cav1) expression contributes to idiopathic PAH, and in animal models, can be alleviated by inhibiting or deleting endothelial nitric oxide synthase (eNOS). Hypothesis: As females are at greater risk of developing PAH but exhibit a more favorable outcome compared to males, we hypothesized that EC Cav1 deficiency in male mice would contribute to EC Cav1-dependent sex differences following chronic hypoxia exposure. Methods: EC-Cav1 -/- mice ( Cdh5.Cre ERT2 ;mTmG;Cav1 f/f injected with tamoxifen; ECKO) vs. wild-type liter mates injected with oil (ECWT), and Cav1 KO, Cav1-RC, and WT mice (6-8 week old) were exposed to 10% O 2 for up to 8 weeks (hypoxia-induced PH (HPH)). Echocardiography, right ventricular systolic pressure (RVSP) and hypertrophy (RVH), lung histology, Western blot, and survival were used to quantify pulmonary and cardiac function. Data were analyzed by two-way ANOVA and Tukey’s post hoc analysis. Results: After 8-weeks of hypoxia exposure, over 90% of male and 40% of female Cav1 KO became moribund, whereas lethality was less than 10% for WT and Cav1 RC mice (p < 0.01). Cav1 ECKO mice exhibited 30% lethality, whereas all ECWT siblings survived. Both Cav1 KO and ECKO mice exhibited a significant increase in pulmonary artery wall thickness, RVH, and RVSP. Hypoxia also reduced PAT and TAPSE, as well as LV systolic and diastolic function, including IVRT, CO, EF, FS, and global longitudinal strain in Cav1 KO and ECKO as compared to WT, ECWT, and Cav1-RC mice indicating EC Cav1 expression is cardioprotective in the context of HPH. In whole lung lysates, we observed reduced eNOS dimerization and an increase in eNOS pSer1179 indicative of eNOS dysfunction under normoxia which was exaggerated following hypoxia exposure to a greater extent in male Cav1 KO and ECKO as compared to Cav1-RC or WT mice. Conclusions: Chronic hypoxia-induced PH and mortality observed in Cav1 KO and ECKO mice is associated with both RV and LV failure and eNOS dysfunction to a greater extent in male mice, which was largely prevented by EC Cav1 expression.

Experimental research on the thermal and mechanical response of flowing pipelines under the horizontal jet flame

The safe operation of parallel pipelines has become a focus of attention. The jet flame generated by the initial pipe accident may cause adjacent pipe section failure. Therefore, it is necessary to study the thermal impact of jet flame on adjacent pipelines. In this paper, we design and establish a thermal effect test platform to determine the change in pipe wall temperature and mechanical properties under the horizontal jet flame. Firstly, the flame combustion characteristics, such as flame form, temperature, and heat flux, are tested and analyzed. Then, the quantitative variation law of the pipe wall and oil temperature under different flow rates, wall thicknesses, and heating lengths is obtained. Combined with the mechanical test results of experimental pipelines, a pipe-bearing capacity calculation model is established via the GA-BP machine learning algorithm. Finally, the safety evaluation method and classification of the stress margin are established. The results indicate that the temperature and heat flux of the fire-facing surface is significantly higher than other clock orientations, where the values are 1287.38 ℃ and 12.37 kW/m2, respectively. As the flow rate decreases and the wall thickness and heating length increase, the pipe wall temperature rises linearly, and the tensile strength and impact toughness reduce logarithmically. The average relative error of the pipe strength prediction model is less than 2.44 %. The established safety evaluation method can be applied to determine the thermal risk level of steel pipelines under the jet flame.