Increased Wall Thickness Research Articles

Abstract 4135476: The Cardiomyocyte Hypertrophy Inhibitor RFN-409, Identified by High Throughput Screening Assay, Suppresses Pressure Overload-induced Systolic Dysfunction in Mice by Suppressing p38 Activity

Purpose: When the heart is exposed to stresses such as myocardial infarction or hypertension, it undergoes compensatory hypertrophy in response. However, continuation of the stress causes this compensatory mechanism to fail, and eventually systolic dysfunction or decompensated heart failure occur. As the hypertrophy of individual cardiomyocytes has been observed in this process, controlling cardiomyocyte hypertrophy is a potential target the prevention and treatment of heart failure. In this study, we constructed a high throughput screening (HTS) assay using cardiomyocyte hypertrophy as an index parameter. Compounds that inhibit cardiomyocyte hypertrophy were selected from our low molecular compound library. Methods and Results: In the primary screening, cultured rat primary cardiomyocytes were treated with each compound at a final concentration of 1 µM and then stimulated with 30 µM phenylephrine (PE) for 48 hours. These cells were subjected to fluorescent immunostaining with α-actinin, and cardiomyocyte area was measured using an ArrayScan™ system. The hypertrophy inhibition rate (%) of each compound was calculated as [(PE(+) - compound) / (PE(+) - PE(-))] × 100. The compounds with a hypertrophy inhibition rate greater than 50% and less than 150% were selected as hit compounds. In the secondary screening, these hit compounds were evaluated based on the dose-dependency of cardiomyocyte hypertrophy inhibition and the inhibition of the mRNA levels of the cardiac hypertrophy response genes ANF and BNP using real-time PCR. From the 269 low molecular-weight compounds in the original compound library, eight were selected through the primary and secondary screenings. Among them, we focused on Reference Number 409 (RFN-409). Western blotting indicated that RFN-409 inhibited PE-induced p38 activation. Next, we investigated the effect of RFN-409 on heart failure. Eight-week-old male C57 BL/6J mice were subjected to transverse aortic constriction (TAC) surgery and then randomly assigned to intraperitoneal treatment with RFN-409 (3, 10 mg/kg) or vehicle for eight weeks. RFN-409 at 10 mg/kg significantly prevented TAC-induced increase in left ventricular posterior wall thickness and decrease in left ventricular fractional shortening. Discussion: RFN-409 suppressed TAC-induced development of heart failure, at least partially by inhibiting p38 activity. These findings suggest that RFN-409 may be an effective agent for heart failure therapy.

An extended variational method for the resistive wall mode in toroidal plasma confinement devices

The external-kink stability of a toroidal plasma surrounded by a rigid resistive wall is investigated. The well-known analysis of Haney and Freidberg is rigorously extended to allow for a wall that is sufficiently thick that the thin-shell approximation does not necessarily hold. A generalized Haney–Freidberg formula for the growth-rate of the resistive wall mode is obtained. Thick-wall effects do not change the marginal stability point of the mode but introduce an interesting asymmetry between growing and decaying modes. Growing modes have growth-rates that exceed those predicted by the original Haney–Freidberg formula. On the other hand, decaying modes have decay-rates that are less than those predicted by the original formula. The well-known Hu–Betti formula for the rotational stabilization of the resistive wall mode is also generalized to take thick-wall effects into account. Increasing wall thickness facilitates the rotational stabilization of the mode, because it decreases the critical toroidal electromagnetic torque that the wall must exert on the plasma. On the other hand, the real frequency of the mode at the marginal stability point increases with increasing wall thickness.

Assessing the utility of the increased wall thickness score in diagnosing ATTR cardiomyopathy: a validation study

Abstract Introduction Cardiac amyloidosis due to transthyretin deposition (ATTR-CM) is often underdiagnosed. An increased left ventricular wall thickness (LVWT) should raise the suspicion for ATTR-CM, but it is a very frequent and non-specific finding. In order to improve diagnostic certainty, an echocardiographic score (Increased Wall Thickness [IWT] score) was recently proposed. The aim of our study was to assess the diagnostic performance of the IWT score in an independent population with increased LVWT. Methods We conducted a retrospective analysis of 295 consecutive patients studied at our centre for increased LVWT. All patients with severe aortic stenosis (AS) had ATTR-CM excluded by endomyocardial biopsy (EMB), during aortic valve replacement. ATTR-CM was considered as per the ESC algorithm. To be included, patients with Hypertrophic Cardiomyopathy (HCM) performed cardiac magnetic resonance and required a sarcomeric mutation for definite diagnosis. The echocardiographic IWT score was calculated for all patients, and categorized as certain (IWT≥8), unlikely (IWT ≤1) or indeterminate (1 < IWT < 8) for ATTR-CM diagnosis. Results A total of 295 patients were included (median age of 75 years [69-81], 61% men). Overall, 230 (70%) patients had hypertension and 164 (56%) chronic kidney disease (CKD). The median LVWT was 16 mm [IQR 15-19] and the median LVEF was 57% [IRQ 50-62%]. After diagnostic workup, 97 patients (33%) had confirmed ATTR-CM, 129 (44%) had isolated severe AS and 71 (24%) had hypertrophic cardiomyopathy (HCM). Fifteen patients had both severe AS and ATTR-CM. The median IWT score was 4 (IQR 2-7), with 21% of patients (n=64) showing an IWT score ≤1, 19% an IWT score ≥8, and 60% of patients (n=176) having an "indeterminate" value between 2 and 7. Despite this, on a continuous scale, the IWT showed good discriminative value (area under ROC curve 0.86, 95% 0.82-0.90, p<0.001). The criteria of IWT score ≥8 showed a positive predictive value of 82% (95% CI 72-89%), while an IWT score ≤ 1 yielded a negative predictive value of 92% (95% CI 84-97%) - Figure. Conclusions Even though the IWT score provides "indeterminate" results in a large proportion of patients, values at the ends of the spectrum showed good negative and positive predictive values for the diagnosis of ATTR-CM. Our findings provide external validation for this echocardiographic score, and support its use in the diagnostic workup of patients with increased wall thickness and suspected ATTR-CM.

AFFECT-HCM: quality of life and costs in hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, characterised by increased wall thickness. Pathogenic DNA variants in sarcomeric genes are identified in about half of HCM patients, enabling pre-symptomatic testing in family members. Since the first description of HCM tremendous progress has been made in the evaluation and management of HCM patients. However, little is known on the impact of HCM on quality of life (QoL) and costs. Purpose The AFFECT-HCM study evaluates the QoL, healthcare and societal costs in HCM patients and genotype-positive phenotype-negative (G+/P-) subjects. Methods The AFFECT-HCM is a multi-centre prospective study including genotyped HCM patients aged 18-80 years and G+/P- subjects. The study cohort is divided into three groups based on phenotype: G+/P- (wall thickness <13 mm), non-obstructive HCM (nHCM, maximal left ventricular outflow tract (LVOT) gradient <30 mmHg) and obstructive HCM (oHCM, LVOT gradient ≥30 mmHg). For QoL, the generic five-domain five-level EQ-5D-5L with the attached visual analogue scale and disease-specific Kansas City Cardiomyopathy Questionnaire are used. Healthcare and societal costs are measured via a bottom-up approach using the cost questionnaires iMCQ and iPCQ and expressed with means (the standard in healthcare cost reporting despite non-normality) in 2023 Euro per patient per year (€ PPPY). QoL and costs are compared between phenotypes. Results Results are summarised in the table. Between November 2022 - December 2023, 506 subjects (mean age 55 years, 39% female) were included in three Dutch hospitals. The study included 84 G+/P-, 307 nHCM and 115 oHCM subjects. Questionnaire response rate was 92%. Compared to G+/P- subjects; HCM patients were older (57 vs 46 yrs), more often male (67% vs 32%) and had more cardiovascular risk factors. Compared to nHCM patients, oHCM patients were more often symptomatic (58% vs 34%), more often in NYHA class III (19% vs 2%) and used more HCM-related medications (79% vs 64%). HCM patients, and particularly oHCM patients, reported decreased QoL with lower QoL-related questionnaire scores (Figure). The utilities (EQ-5D-5L) of HCM patients were lower than G+/P- subjects and the Dutch overall average (0.87±0.17), and for oHCM comparable with another study (0.82±0.18). Costs were higher for HCM patients than G+/P- subjects (€14374 vs €5888 PPPY) and higher in oHCM patients compared to nHCM patients (€19672 vs €12419 PPPY). The leading between-group difference is higher productivity losses in oHCM patients. Conclusion HCM is associated with reduced QoL and increased costs, especially in oHCM patients. The primary cost driver are healthcare costs, but the difference between oHCM and nHCM patients is mainly caused by indirect costs due to productivity losses. These data provide novel insights in the BoD of HCM and can aid in assessing cost-effectiveness analyses of new therapies for HCM in the future.Baseline characteristics and resultsQuality of life-related questionnaires

Prevalence of transthyretin amyloid cardiomyopathy in patients hospitalised for heart failure with preserved ejection fraction in an LATAM center

Abstract Introduction Transthyretin Amyloid cardiomyopathy (ATTR-CM) usually presents as heart failure with preserved ejection fraction (HFpEF). Its diagnosis has a significant clinical impact, as specific treatment is currently available. Purpose To assess the prevalence of ATTR-CM in patients hospitalised for HFpEF and increased septal thickness in our institution of general community hospital in Latin America (LATAM). Methods Cross-sectional study. Patients hospitalised for HFpEF (>50%) and septal thickness ≥ 12 mm during the period from 8/2019 to 1/2023 were prospectively included. Patients with pacemaker, significant left valve disease and end-stage renal failure (creatinine clearance < 30 ml/min/BSA) were excluded. A pyrophosphate bone scintigraphy (PYP) was planned to be performed in order to assess ATTR-CM. The prevalence of ATTR-CM and its 95% confidence interval were calculated. Results A PYP was performed in 59/82 patients hospitalised for HFpEF. Median age was 85 [IQR 78-88] years, and 54% were women. At admission, 61% (n=36) had atrial fibrillation and the median NT Pro-Bnp was 3536 [1700-7748] pg/mL. The mean left ventricle ejection fraction was 57% (+/- 5%). The prevalence of ATTR-CM diagnosed by PYP was 19% (95% CI 9.7-30.1, n=11). There were no significant clinical differences between patients who performed a PYP and did not. Patients with ATTR-CM had lower blood pressure and higher septal thickness, NT Pro-Bnp and troponin levels compared to patients without ATTR-CM (TABLE). Conclusion In patients admitted for HFpEF and increased septal thickness, the diagnosis of ATTR-CM was relatively common (one of five had ATTR-CM) in our region (LATAM). We believe that systemic assessment with PYP should be performed in patients hospitalised with HFpEF and increased wall thickness.

Physiological and biochemical responses in a cadmium accumulator of traditional Chinese medicine Ligusticum sinense cv. Chuanxiong under cadmium condition

Ligusticum sinense cv. Chuanxiong (L. Chuanxiong), one of the widely used traditional Chinese medicines (TCM), is currently facing the problem of excessive cadmium (Cd) content. This problem has significantly affected the quality and safety of L. Chuanxiong and become a vital factor restricting its clinical application and international trade development. Currently, to solve the problem of excessive Cd, it is essential to research the response mechanisms of L. Chuanxiong to Cd stress. However, there are few reports on its physiological and biochemical responses under Cd stress. In this study, we conducted the hydroponic experiment under 25 μM Cd stress, based on the Cd content of the genuine producing areas soil. The results showed that 25 μM Cd stress not only had no significant inhibitory effect on the growth of L. Chuanxiong seedlings but also significantly increased the chlorophyll a content (11.79%) and root activity (51.82%) compared with that of the control, which might be a hormesis effect. Further results showed that the absorption and assimilation of NH4+ increased in seedlings under 25 μM Cd stress, which was associated with high photosynthetic pigments. Here, we initially hypothesized and confirmed that Cd exceedance in the root system of L. Chuanxiong was due to the thickening of the root cell wall, changes in the content of the cell wall components, and chelation of Cd by GSH. There was an increase in cell wall thickness (57.64 %) and a significant increase in cellulose (25.48%) content of roots under 25 μM Cd stress. In addition, L. Chuanxiong reduced oxidative stress caused by 25 μM Cd stress mainly through the GSH/GSSG cycle. Among them, GSH-Px (48.26%) and GR (42.64%) activities were significantly increased, thereby maintaining a high GSH/GSSG ratio. This study preliminarily reveals the response of L. Chuanxiong to Cd stress and the mechanism of Cd enrichment. It provides a theoretical basis for solving the problem of Cd excessive in L. Chuanxiong.Graphical Physiological and biochemical mechanisms of L. Chuanxiong seedlings under Cd stress.

Study on Crashworthiness of Shrink Tube Anti-Creep Device

Based on the requirements of the narrow installation space of a train end, compact energy-absorbing travel, and huge energy suck, a shrink tube anti-creep device was designed. The crashworthiness of different structures was studied by means of a material test, a trolley test, and numerical simulation. For every 1 mm increase in tube wall thickness, 1 mm increase in the axial length of the friction cone, and 0.01 increase in the friction coefficient, the mean crushing force (MCF) increased by 45.1 kN, 13.5 kN, and 30.5 kN, respectively. When the cone angle of the shrink tube increased from α = 5° to α = 25°, the increase in the MCF with different thicknesses was about 600%. The MCF was most affected by the cone angle, followed by the wall thickness, the friction coefficient, and the axial length of the friction cone. The change in the contact length of the friction cone of the shrink tube under different structural parameters was compared. The contact length decreased with the increase in tube wall thickness and increased with the increase in angle. The variation rule of MCF was obtained to provide a reference for the development of genealogical products.

Investigation on the influence of GPI-AP for the production of malic acid in Aspergillus niger

Based on the potential of microbial fermentation in the sustainable and environmentally friendly production of L-malic acid (L-MA), this study aims to investigate the effect of glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) on enhancing the stability of Aspergillus niger (A. niger) cell wall to increase L-MA production. Through experiments, we discovered and screened GPI2, a GPI-anchored cell surface glycoprotein, and confirmed for the first time that it has a promoting effect on L-MA, a metabolite of A. niger. This recombinant strain RG0098 that overexpressed gpi2 showed an increase in cell wall thickness and robustness, a decrease in intracellular reactive oxygen species (ROS) levels, which improved the antioxidant capacity. After 108 h of fermentation, the production of L-MA reached 114.7 ± 2.12 g/L, and the productivity was 1.06 ± 0.025 g/L/h. The strain RG0098 has enhanced the productivity of L-MA by a notable margin of 49.7 %. This study provides a sustainable and environmentally friendly pathway for the production of L-MA through microbial fermentation.

Characteristics and impacts of dental implant displacement into the maxillary sinus

Background/purposeDental implants displaced into the maxillary sinus are considered to require surgical removal as the treatment of choice. However, displaced implants have been reported to affect the maxillary sinus in different ways. This study aimed to evaluate characteristics and impacts of dental implant displacement into the maxillary sinus. Materials and methodsFourteen sinuses with displaced implants into the maxillary sinus were included. Demographic data and radiographic images were analyzed, with a focus on the impact of various factors such as demographic data, timing of displacement, duration of retention, and residual bone height on maxillary sinus opacification and sinus wall thickness. ResultsImplants were displaced during or in the early stage after implant placement in 9 cases and after functional loading in 5 cases. Radiographic evaluations showed higher sinus opacification score (P = 0.019) and increased wall thickness (P = 0.198) in cases with displacement after functional loading, although the difference in wall thickness was not statistically significant. When the duration of implant retention in the sinus was longer, higher sinus opacification and sinus wall thickness were observed, although the differences were not statistically significant. Univariate regression analysis demonstrated that the timing of displacement significantly influenced maxillary sinus opacification (P = 0.013) and sinus wall thickness (P = 0.013). For all cases, evidence of site preparation and the use of short implants were not observed. ConclusionThis study suggests that adequate pre-implant site preparation and timely intervention are essential to prevent and manage implant displacement into the maxillary sinus.

Tangent hyperbolic MHD nanoliquids on non-isothermal stretched sheets: Analyzing the impact of transport parameters, variable fluid properties and convective boundary conditions

The key focus of this research is to look at how tangent hyperbolic magnetohydrodynamic (MHD) nano-liquids move in a non-isothermal coagulated stretched sheet. In this study, we intend to explore how fluid behavior responds to alternations in transport physical parameters. The coagulated sheet is subjected to two distinct boundary conditions to inspect the heat and mass transport rate of the nano liquid. The convective heat boundary condition (CBC) and mass-convective boundary condition (MCBC) are employed to specify the physical conditions at the boundaries of the problem domain. The boundary conditions, responsible for regulating heat flow and mass transfer rates, play a crucial role in shaping the liquid’s behavior. Using a similarity solution, the partial differential equation describing the flow of mass and heat within the system transforms into an interconnected network of non-linear ordinary differential equations. These mathematical equations are subsequently figured out using a numerical finite difference method. This study additionally examines the correlation between thermophoresis and Brownian motion, two fundamental concepts in the dynamics of colloidal suspensions. The study’s findings indicate that the temperature profile increases in all scenarios when the variable thermal conductivity and variable viscosity parameters are increased. In contrast, for the same parameters, the velocity profile is decreased. Further, increasing wall thickness reduces heat dissipation; consequently, the temperature profile similarly affects the velocity power index. The Biot number improves the rates of temperature transfer. These results underscore the significant influence of these parameters in predicting the behavior of MHD tangent hyperbolic nanofluids. This study elucidates the intricate interaction among different physical parameters in the dynamics of nano liquids, which holds significant implications for various industrial applications.

Current Overview of the Biology and Pharmacology in Sugen/Hypoxia-Induced Pulmonary Hypertension in Rats.

The Sugen 5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) demonstrates most of the distinguishing features of PAH in humans, including increased wall thickness and obstruction of the small pulmonary arteries along with plexiform lesion formation. Recently, significant advancement has been made describing the epidemiology, genomics, biochemistry, physiology, and pharmacology in Su/Hx challenge in rats. For example, there are differences in the overall reactivity to Su/Hx challenge in different rat strains and only female rats respond to estrogen treatments. These conditions are also encountered in human subjects with PAH. Also, there is a good translation in both the biochemical and metabolic pathways in the pulmonary vasculature and right heart between Su/Hx rats and humans, particularly during the transition from the adaptive to the nonadaptive phase of right heart failure. Noninvasive techniques such as echocardiography and magnetic resonance imaging have recently been used to evaluate the progression of the pulmonary vascular and cardiac hemodynamics, which are important parameters to monitor the efficacy of drug treatment over time. From a pharmacological perspective, most of the compounds approved clinically for the treatment of PAH are efficacious in Su/Hx rats. Several compounds that show efficacy in Su/Hx rats have advanced into phase II/phase III studies in humans with positive results. Results from these drug trials, if successful, will provide additional treatment options for patients with PAH and will also further validate the excellent translation that currently exists between Su/Hx rats and the human PAH condition.

Study on the influence of slit pipe wall thickness on the rock breaking effect of slit charge explosion

AbstractIn this study, the influence of slit pipe wall thickness on shaped charge blasting efficiency was investigated. The influence of different slit pipe wall thicknesses on the dynamic behavior of slotted charge blasting was analyzed by a combination of experimental observations and numerical simulations. Polymethyl methacrylate (PMMA) was used as a rock simulation material to prepare slit pipes with different slit pipe wall thicknesses (0.5, 1.0, and 1.5 mm). A dynamic caustics system is used to capture the crack propagation process. ANSYS/LS‐DYNA was used for the numerical simulation analysis. The experimental results show that there is a positive correlation between the slit pipe wall thickness and the crack propagation length, velocity, and dynamic stress intensity factor. With increasing slit pipe wall thickness, the directional propagation and energy concentration ability of cracks are significantly improved, but an increase in the slit pipe wall thickness will also promote the propagation of secondary cracks. In addition, the numerical simulation results support the experimental observations and reveal the existence of an optimal slit pipe wall thickness that can maximize the blasting efficiency while maintaining structural integrity. This study not only deepens the understanding of the physical laws of the blasting process but also provides a practical reference for the optimal design of slotted charges in engineering applications.

Associations between visceral and liver fat and cardiac structure and function: a UK Biobank study.

Different fat depots have connected to cardiovascular health. We assessed the associations of abdominal magnetic resonance-quantified visceral adipose tissue (VAT) and liver fat (proton density fat fraction, PDFF) with cardiac magnetic resonance (CMR)-measured cardiac structure and function, and considered potential mechanism. Our study encompassed 10,920 participants from the UK Biobank. We utilized multiple linear regression and multiple mediation analyses to estimate the connections between VAT or PDFF and CMR metrics. Elevated VAT or PDFF exhibited associations with adverse left ventricular (LV) structure (increased wall thickness, concentric LV remodeling), impaired LV function (lower LV global functional index, absolute value of LV global longitudinal strain), and diminished left atrial volumes and stroke volume (all p-values were significant）. Upon stratifying participants based on VAT and PDFF combinations, all groups, except the low VAT-low PDFF group, were linked to unfavorable cardiac remodeling metrics. The high VAT-high PDFF group displayed the most pronounced cardiac alterations. Multiple mediation analyses were employed to investigate potential mediating roles of systolic blood pressure (SBP), diabetes, dyslipidemia and blood biomarkers (lipidemia, transaminases) in the adipose-CMR relationship. The findings suggested that VAT or PDFF was related to SBP, diabetes, dyslipidemia, lipid profile, liver function, and glucose. Several potential mediating pathways were identified, primarily through SBP and triglyceride-glucose index, which only partially explained the adipose-CMR relationship. We established the independent associations of VAT and PDFF with unhealthy cardiac structure and function. Furthermore, it identifies SBP and insulin resistance as important mediating factors.

Crashworthiness analysis of hierarchically reinforced double-square tubes under axial impact

Two strategies are proposed to design new hierarchically reinforced double-square tubes (HRDST). Strategy A: adding triangles from inside to outside in one direction. Strategy B: adding triangles along both the outer and inner quadrilateral directions at the same time. Their crashworthiness analyses are carried out under the conditions of the same wall thickness and the same mass. The results show that the proposed double square tubes, combined with the gradient hierarchical design, can effectively improve the crashworthiness of the structure under both conditions. The improvement of strategy B is more significant than that of strategy A. The energy absorption (EA), specific energy absorption (SEA), and crushing force efficiency (CFE) and initial peak crush force (IPCF) of HRDSTB-3 are improved by 2343.87%, 493.17%, 573.74% and 262.73%, respectively, under the same wall thickness. The EA, SEA, CFE of HRDSTB-3 also increased by 111.23%, 111.23%, and 226.34%, respectively, for the same mass, while the IPCF decreased by 35.27%. The parametric study shows that the effect of wall thickness on structural crashworthiness is significant, but the rate of increase between two adjacent wall thicknesses decreases as the wall thickness increases. The inner and outer edge length ratios (k) also have a substantial effect on structural crashworthiness, with SEA and CFE being 24.42% and 23.47% higher for k = 5/12 compared to k = 8/12 for HRDSTA-3, and 29.24% and 27.55% higher for k = 4/12 compared to k = 8/12 for HRDSTB-3. Finally, comparing HRDSTA-3 and HRDSTB-3 with other square-layered multicellular designs, the results show that the two designs proposed in this paper, combining double square tubes with gradient hierarchies, exhibit better crashworthiness. Compared with MSTL2-2, the SEA of HRDSTA-3 and HRDSTB-3 are 27.98% and 33.01% higher, respectively, and the CFE is 27.86% and 32.96% higher, respectively.

The Mayo ATTR-CM score versus other diagnostic scores and cardiac biomarkers in patients with suspected cardiac amyloidosis.

Several scores were developed to help the diagnosis of cardiac amyloidosis (CA). The most recent one, being the Mayo transthyretin amyloidosis cardiomyopathy (ATTR-CM) score, was not externally validated. We compared the diagnostic performance of the ATTR-CM score with previous tools (increased wall thickness [IWT] score, AMYLoidosis Index [AMYLI] score, and cardiac biomarkers) in a cohort of patients evaluated for a suspicion of CA. We analysed 362 consecutive patients referred to a third-level centre for suspected CA. Overall, 132 (36%) had transthyretin CA (ATTR-CA), and 91 (25%) immunoglobulin light chain CA (AL-CA); CA was excluded in 139 (38%). ATTR-CM score had a good diagnostic performance to distinguish ATTR-CA from AL-CA or no CA, with an area under the curve (AUC) of 0.795 (95% confidence interval [CI] 0.747-0.842, p < 0.001), and ATTR-CA from no CA (AUC 0.822, 95% CI 0.774-0.871, p < 0.001). Results were consistent in both patients with preserved (AUC 0.787, 95% CI 0.726-0.848, p < 0.001), and reduced or mildly reduced ejection fraction (AUC 0.790, 95% CI 0.709-0.871, p < 0.001). The ATTR-CM score showed a better discrimination compared to IWT and AMYLI score to distinguish ATTR-CA from AL-CA or no CA (p = 0.002), but not to distinguish ATTR-CA from no CA (p = 0.270). Diagnostic accuracy was significantly higher for the ATTR-CM score as compared to the rule-in cut-off of high-sensitivity troponin T. The Mayo ATTR-CM score has a good performance in identifying patients with ATTR-CA, with also better discrimination power when compared to other scores and biomarkers.

Sex differences and role of lysyl oxidase-like 2 in angiotensin II-induced hypertension in mice.

Hypertension, a disease with known sexual dimorphism, accelerates aging-associated arterial stiffening, partly because of the activation of matrix remodeling caused by increased biomechanical load. In this study, we tested the effect of biological sex and the role of the matrix remodeling enzyme lysyl oxidase-like 2 (LOXL2) in hypertension-induced arterial stiffening. Hypertension was induced by angiotensin II (ANG II) infusion via osmotic minipumps in 12- to 14-wk-old male and female mice. Blood pressure and pulse wave velocity (PWV) were measured noninvasively. Wire myography and uniaxial tensile testing were used to test aortic vasoreactivity and mechanical properties. Aortic wall composition was examined by histology and Western blotting. Uniaxial stretch of cultured cells was used to evaluate the effect of biomechanical strain. LOXL2's catalytic function was examined using knockout and inhibition. ANG II infusion-induced hypertension in both genotypes and sexes. Wild-type (WT) males exhibited arterial stiffening in vivo and ex vivo. Aortic remodeling with increased wall thickness, intralamellar distance, higher LOXL2, and collagen I and IV content was noted in WT males. Female mice did not exhibit increased PWV despite the onset of hypertension. LOXL2 depletion improved vascular reactivity and mechanics in hypertensive males. LOXL2 depletion improved aortic mechanics but worsened hypercontractility in females. Hypertensive cyclic strain contributed to LOXL2 upregulation in the cell-derived matrix in vascular smooth muscle cells (VSMCs) but not endothelial cells. LOXL2's catalytic function facilitated VSMC alignment in response to biomechanical strain. In conclusion, in males, arterial stiffening in hypertension is driven both by VSMC response and matrix remodeling. Females are protected from PWV elevation in hypertension. LOXL2 depletion is protective in males with improved mechanical and functional aortic properties. VSMCs are the primary source of LOXL2 in the aorta, and hypertension increases LOXL2 processing and shifts to collagen I accumulation. Overall, LOXL2 depletion offers protection in young hypertensive males and females.NEW & NOTEWORTHY We examined the effect of sex on the evolution of angiotensin II (ANG II)-induced hypertension and the role of lysyl oxidase-like 2 (LOXL2), an enzyme that catalyzes matrix cross linking. While ANG II led to hypertension and worsening vascular reactivity in both sexes, aortic remodeling and stiffening occurred only in males. LOXL2 depletion improved outcomes in males but not females. Thus males and females exhibit a distinct etiology of hypertension and LOXL2 is an effective target in males.

First report of the clinical characteristics and outcomes of cardiac amyloidosis in Saudi Arabia.

Cardiac amyloidosis (CA) is a potentially fatal multisystemic disease that remains significantly underdiagnosed, particularly in the Middle East. This study aims to evaluate the prevalence and clinical characteristics of CA in a high-risk population at a tertiary centre in Saudi Arabia. This cross-sectional, retrospective, single-centre study was conducted at a tertiary hospital in Riyadh, Saudi Arabia. We reviewed the medical records of heart failure patients seen between August 2018 and July 2022 who exhibited red flags for CA and subsequently underwent CA screening. Red flags that prompted the workup included at least two of the following factors: the presence of unilateral or bilateral carpal tunnel syndrome, a family history of transthyretin amyloid (ATTR) amyloidosis and specific electrocardiographic features (relative/absolute low QRS voltage, pseudoinfarct pattern and atrioventricular/interventricular conduction abnormalities). Echocardiographic red flags included mainly increased wall thickness (≥12mm), significant diastolic dysfunction, reduced left ventricular (LV) longitudinal function, right ventricular (RV) dysfunction and elevated right atrial (RA)/pulmonary artery (PA) pressure. Cardiac magnetic resonance (CMR) red flags included aspects similar to those in an echocardiogram as well as a subendocardial or transmural late gadolinium enhancement (LGE) pattern. These patients were assessed for CA through technetium-99m pyrophosphate ([99mTc]Tc-PYP) bone scintigraphy, serum and urine protein electrophoresis with immunofixation and a serum-free light chain assay. A total of 177 patients were screened, of which 21.0 (11.9%) patients were diagnosed with transthyretin amyloid CA (ATTR-CA) and 13 (7.3%) patients were diagnosed with light chain CA (AL-CA). Compared with patients with negative/equivocal [99mTc]Tc-PYP scans (grades 0-1), patients with positive [99mTc]Tc-PYP scans (grades 2-3) were older (78.0 vs. 68.0years, P<0.001), had higher levels of troponin (P=0.003) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (P<0.001), had a higher LV mass index (P<0.001), displayed a more depressed global longitudinal strain (GLS) (P<0.001) with a greater prevalence of a relative apical sparing pattern (P<0.001) and demonstrated a higher incidence of first-degree atrioventricular block (P=0.008) and low voltage patterns on electrocardiography (P<0.001). Patients with ATTR-CA and AL-CA were more likely to have a subendocardial or transmural LGE pattern on CMR (P<0.001) and had a significantly lower overall survival (P<0.001) when compared with other heart failure aetiologies. This is the first study to describe the clinical characteristics and outcomes of CA in the Middle East and Saudi Arabia. The prevalence of CA among screened heart failure patients here aligns with major international studies, suggesting significant underdiagnosis in the region. Therefore, larger multicentric studies and regional screening programmes are urgently needed to accurately characterize the epidemiology and outcomes of CA in the Middle East.

Effects of foliar treatments with urea and nano-urea on the cell walls of Monastrell grape skins

Cell wall composition can be affected by nitrogen availability in the vineyard. Foliar application of urea is effective in supplying nitrogen needs and increasing the nitrogen content of musts. Due to the low recoveries of urea fertilisation, more effective application methods such as the use of nanotechnology are needed. In this work, the effect on the composition of Monastrell grape skin cell walls, after foliar application of urea and amorphous calcium phosphate nano-particles doped with urea was studied. The treatments with urea and nano-urea, although the urea content in the nano-treatment was eight times lower than in the conventional treatment, produce an equivalent modification of the cell wall. In fact, both treatments produced an increase in cell wall thickness and in cell wall composition, contents of proteins, hemicellulose and uronic acids also increased. However, phenolic compounds were not affected and cellulose showed lower concentrations than control grapes. Regarding the spectrophotometric parameters of the wine studied, the anthocyanins content and colour intensity were reduced in wines with both treatments and the total polyphenol index was slightly affected.

Host-induced cell wall remodeling impairs opsonophagocytosis of Staphylococcus aureus by neutrophils.

Understanding how bacteria adapt to the host environment is critical in determining fundamental mechanisms of immune evasion, pathogenesis, and the identification of targets for new therapeutic approaches. Previous work demonstrated that Staphylococcus aureus remodels its cell envelope in response to host factors and we hypothesized that this may affect recognition by antibodies and thus killing by immune cells. As expected, incubation of S. aureus in human serum resulted in rapid binding of antibodies. However, as bacteria adapted to the serum, the increase in cell wall thickness resulted in a significant reduction in exposure of bound antibodies. This reduced antibody exposure, in turn, led to reduced killing by human neutrophils. Importantly, while antibodies bound to some cell surface structures became obscured, this was not the case for those bound to wall teichoic acid, which may have important implications for vaccine design.

Multiscale-mechanical analysis on self-healing microcapsules under asphalt pavement

To investigate the stress state of self-healing microcapsules in asphalt pavement during their operational phase, this study utilizes the finite difference method to establish a macroscopic structural model of asphalt pavement and a multi-scale model of representative volume elements (RVE)containing self-healing microcapsules. It systematically analyzes the effects of microcapsule content, capsule wall modulus, and wall thickness on the its mechanical performance under different asphalt pavement. Experimental findings indicate that an increase in microcapsule content initially increases and subsequently decreases the maximum principal stress and shear stress of the capsule wall, suggesting an optimal content range for achieving optimal mechanical response. Moreover, an increase in capsule wall modulus results in increased maximum principal stress, minimum principal stress, and maximum shear stress borne by the capsule wall, underscoring the importance of capsule wall modulus for the mechanical properties of microcapsules. The impact of increasing wall thickness on minimum principal stress shows an initial increase followed by a decrease, emphasizing the critical role of appropriate wall thickness selection in facilitating prompt response of microcapsules to pavement cracks. This research provides essential theoretical foundations for the design and application of microcapsules, thereby enhancing the self-healing capability of asphalt pavement.