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Background: Aberrant occlusion and aging are two main risks for temporomandibular joint (TMJ) degeneration. Objective: To assess the combined impact of occlusion and age on TMJ disc. Methods: To avoid the confounding impact of gender, presently, 126 female C57BL/6J mice, 63 youngsters, 6‐week old and 63 adults, 28‐week old, were used. An experimental bilateral anterior crossbite (BAC) relation was created by installing metal tubes onto the mandibular incisors. Mice were sacrificed at 3, 7 and 11 weeks (n = 9). Additionally, the installed tubes were removed at 7 weeks in removal groups and the TMJs were sampled after another 4 weeks (n = 9). Disc changes were detected by histomorphology, immunohistochemistry, and western blot assays. Results: Disc deformation was obvious in BAC groups. The typical change was hyperplasia at the posterior region of the disc where there was significant infiltration of inflammatory cells. Expressions of the inflammatory markers, including tumour necrosis factor‐α and interleukin‐1β, and the catabolic markers, including fibronectin (FN), FN N‐terminal fragments, and vascular endothelial growth factor‐A, were all increased. The changes were more obvious in adults than in youngsters. Removal of BAC attenuated inflammatory and catabolic changes in the youngsters, but the inflammatory markers recovered little in the adults. Conclusion: TMJ disc responds to BAC by degeneration and inflammation, and respond to BAC removal by rehabilitation. Adult discs show severer degeneration responses to BAC and a lower level of anti‐inflammatory capability to BAC removal than the youngster's discs. Animals cannot be equated with humans. The human disc response to occlusion changes worth further exploration. [ABSTRACT FROM AUTHOR]

Abstract Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysed patients. AVF is created surgically using the patient’s artery and vein. Once the connection (anastomosis) is made, the maturation process begins. Studies have shown that most AVFs do not survive beyond one year. This study presents fluid–structure interaction (FSI) modelling of non-Newtonian blood flow through an end-to-side radio-cephalic AVF, investigated weekly during a 15-week follow-up period and 1.5 years postoperatively using ultrasound methods. The aim was to collect qualitative and quantitative data regarding changes in hemodynamics and alterations in the walls of AVF vasculature. Different material properties were assigned to the artery, suture zone (anastomosis), and vein, while the stiffening of the venous arm over time was also modelled. The proposed FSI methodology can be implemented in future follow-up studies involving groups of patients. The main findings revealed: a) counter-rotating vortices in the anastomosis cross-section affecting local pressure conditions; b) different temporal progression of vorticity, shear strain rate, and turbulent kinetic energy and similarity of the temporal progression of WSS obtained under the assumptions of the rigid-walled and FSI; c) a negligible low-WSS zone in the presented thrombosis-free AVF; d) migration of the zone of maximal temporal wall deformation over time.

Abstract Aims The trials upon which recommendations for the use of cardiac resynchronization therapy (CRT) in heart failure used optimal medical therapy (OMT) before sodium‐glucose co‐transporter 2 inhibitors (SGLT2i). Moreover, the SGLT2i heart failure trials included only a small proportion of participants with CRT, and therefore, it remains uncertain whether SGLT2i should be considered part of OMT prior to CRT. Methods and results We compared electrocardiogram (ECG) and echocardiographic responses to CRT as well as hospitalization and mortality rates in consecutive patients undergoing implantation at a large tertiary centre between January 2019 to June 2022 with and without SGLT2i treatment. Three hundred seventy‐four participants were included aged 74.0 ± 11.5 years (mean ± standard deviation), with a left ventricular ejection fraction (LVEF) of 31.8 ± 9.9% and QRS duration of 161 ± 29 ms. The majority had non‐ischaemic cardiomyopathy (58%) and were in NYHA Class II/III (83.6%). These characteristics were similar between patients with (n = 66) and without (n = 308) prior SGLT2i treatment. Both groups demonstrated similar evidence of response to CRT in terms of QRS duration shortening, and improvements in LVEF, left ventricular end‐diastolic inner‐dimension (LVIDd) and diastolic function (E/A and e/e′). While there was no difference in rates of hospitalization (for heart failure or overall), mortality was significantly lower in patients treated with SGLT2i compared with those who were not (6.5 vs. 16.6%, P = 0.049). Conclusions We observed an improvement in mortality in patients undergoing CRT prescribed SGLT2i compared with those not prescribed SGLT2i, despite similar degrees of reverse remodelling. The authors recommend starting SGLT2i prior to CRT implantation, where it does not delay implantation.

Abstract Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic bronchitis, emphysema and vascular remodelling. The disease is associated with hypoxia, inflammation and oxidative stress. Lung fibroblasts are important cells in remodelling processes in COPD, as main producers of extracellular matrix proteins but also in synthesis of growth factors and inflammatory mediators. Methods In this study we aimed to investigate if there are differences in how primary distal lung fibroblasts obtained from COPD patients and healthy subjects respond to hypoxia (1% O2) and pro-fibrotic stimuli with TGF-β1 (10 ng/mL). Genes and proteins associated with oxidative stress, endoplasmic reticulum stress, remodelling and inflammation were analysed with RT-qPCR and ELISA. Results Hypoxia induced differences in expression of genes involved in oxidative stress (SOD3 and HIF-1α), ER stress (IRE1, PARK and ATF6), apoptosis (c-Jun and Bcl2) and remodelling (5HTR2B, Collagen7 and VEGFR2) in lung fibroblasts from COPD subjects compared to control subjects, where COPD fibroblasts were in general less responsive. The release of VEGF-C was increased after hypoxia, whereas TGF-β significantly reduced the VEGF response to hypoxia and the release of HGF. COPD fibroblasts had a higher release of IL-6, IL-8, MCP-1 and PGE2 compared to lung fibroblasts from control subjects. The release of inflammatory mediators was less affected by hypoxia, whereas TGFβ1 induced differences in inflammatory profile between fibroblasts from COPD and control subjects. Conclusion These results suggest that there is an alteration of gene regulation of various stress responses and remodelling associated mediator release that is related to COPD and hypoxia, where fibroblasts from COPD patients have a deficient response.

Purpose: Endurance elite athletes are expected to present a cardiac remodelling, characterized by eccentric hypertrophy (EH), may be associated with higher sportive performances. However, not all can present a cardiac remodelling. The study aimed to identify endurance athletes without cardiac remodelling characterizing their physiologic and clinical features. Methods: We studied 309 endurance athletes (cycling, rowing, canoeing, triathlon, athletics, long-distance swimming, cross-country skiing, mid-long distance track, pentathlon, biathlon, long-distance skating and Nordic-combined) examined during period of training, by clinical evaluation, ECG, echocardiogram and exercise-stress test. Sport career achievements (Olympic\World championship medals or national\world records) were recorded. Results: EH was found in most of athletes, (n = 126, 67% of males; n = 85, 68.5% of females). A significant proportion,, exhibited normal geometry (NG) (n = 59, 31.3% in males; n = 39, 31.4% in females). At stress test, significant differences between EH and NG athletes were found in peak power (317.1 ± 71.2W in NG vs. 342.2 ± 60.6W in EH, p = 0.014 in males and 225.1 ± 38.7W in NG vs. 247.1 ± 37W in EH, p = 0.003 in females), rest heart rate (66.1 ± 13 in NG vs. 58.6 ± 11.6 in EH, p = 0.001 in males and 68 ± 13.2 in NG vs. 59.2 ± 11.2 in EH, p = 0.001 in females) with similar ventricular extrasystoles (p = 0.363 in males and p = 0.492 in females). However, no significant differences in athletic achievements were registered. Conclusion: Our study demonstrates a relatively high prevalence of NG in endurance athletes, in addition to the expected EH. Athletes with NG perform worse in exercise-stress test and exhibit some less advantageous functional heart characteristics. However, the type of heart geometry is not associated with negative clinical findings. [ABSTRACT FROM AUTHOR]

Aims Pulmonary vascular and right ventricular (RV) remodelling processes are important for development and progression of pulmonary hypertension (PH). The current study analysed the functional role of the extra domain A-containing fibronectin (ED-A+ Fn) for the development of PH by comparing ED-A+ Fn knockout (KO) and wild-type (WT) mice as well as the effects of an antibody-based therapeutic approach in a model of monocrotaline (MCT)-induced PH, which will be validated in a model of Sugen 5416/hypoxia-induced PH. Methods and results PH was induced using MCT (PH mice). Sixty-nine mice were divided into the following groups: sham-treated controls (WT: n = 7; KO: n = 7), PH mice without specific treatment (WT: n = 12; KO: n = 10), PH mice treated with a dual endothelin receptor antagonist (macitentan; WT: n = 6; KO: n = 11), WT PH mice treated with the F8 antibody, specifically recognizing ED-A+ Fn, (n = 8), and WT PH mice treated with an antibody of irrelevant antigen specificity (KSF, n = 8). Compared to controls, WT_PH mice showed a significant elevation of the RV systolic pressure (P = 0.04) and RV functional impairment including increased basal RV (P = 0.016) diameter or tricuspid annular plane systolic excursion (P = 0.008). In contrast, KO PH did not show such effects compared to controls (P = n.s.). In WT_PH mice treated with F8, haemodynamic and echocardiographic parameters were significantly improved compared to untreated WT_PH mice or those treated with the KSF antibody (P < 0.05). On the microscopic level, KO_PH mice showed significantly less tissue damage compared to the WT_PH mice (P = 0.008). Furthermore, lung tissue damage could significantly be reduced after F8 treatment (P = 0.04). Additionally, these findings could be verified in the Sugen 5416/hypoxia mouse model, in which F8 significantly improved echocardiographic, haemodynamic, and histologic parameters. Conclusion ED-A+ Fn is of crucial importance for PH pathogenesis representing a promising therapeutic target in PH. We here show a novel therapeutic approach using antibody-mediated functional blockade of ED-A+ Fn capable of attenuating and partially reversing PH-associated tissue remodelling. [ABSTRACT FROM AUTHOR]

Purpose: Three-dimensional (3D) capacity for remodelling in cubitus varus deformity (CVD) after paediatric supracondylar humeral fractures (PSHFs) remains unelucidated. This study investigated remodelling patterns after PSHFs by examining 3D deformity distribution over time after injury. Methods: Computed tomography (CT) data of 86 patients with CVD after PSHFs were analysed. The 3D deformity angles in the sagittal, coronal, and axial directions were assessed and correlated with the duration between the age at injury and CT evaluation. For the subgroup analysis, we performed the same correlation analysis in a younger (< 8 years old) and an older group (≥ 8 years old); we categorized the duration into early (< 2 years), middle (≥ 2 to < 5 years), and late periods (≥ 5 years) and compared the deformity angles of each direction among the three groups. Results: Sagittal deformity showed a moderate correlation with the duration of deformity (r = -0.54; P < 0.001), while coronal and axial deformities showed a negligible correlation. Sagittal deformity showed moderate correlations with the duration in the younger group (r = -0.62; P < 0.001) and weak correlations in the older group (r = -0.37; P = 0.091). In the sagittal direction, the deformity angle in the early period was significantly larger than those in the mid and late periods (P < 0.001). However, there were no significant differences among the three groups in the coronal and axial directions. Conclusion: Sagittal deformities in CVDs are capable of remodelling, especially in the early period and at a younger age, whereas coronal and axial deformities are less likely to undergo remodelling. [ABSTRACT FROM AUTHOR]

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Aims: The trials upon which recommendations for the use of cardiac resynchronization therapy (CRT) in heart failure used optimal medical therapy (OMT) before sodium‐glucose co‐transporter 2 inhibitors (SGLT2i). Moreover, the SGLT2i heart failure trials included only a small proportion of participants with CRT, and therefore, it remains uncertain whether SGLT2i should be considered part of OMT prior to CRT. Methods and results: We compared electrocardiogram (ECG) and echocardiographic responses to CRT as well as hospitalization and mortality rates in consecutive patients undergoing implantation at a large tertiary centre between January 2019 to June 2022 with and without SGLT2i treatment. Three hundred seventy‐four participants were included aged 74.0 ± 11.5 years (mean ± standard deviation), with a left ventricular ejection fraction (LVEF) of 31.8 ± 9.9% and QRS duration of 161 ± 29 ms. The majority had non‐ischaemic cardiomyopathy (58%) and were in NYHA Class II/III (83.6%). These characteristics were similar between patients with (n = 66) and without (n = 308) prior SGLT2i treatment. Both groups demonstrated similar evidence of response to CRT in terms of QRS duration shortening, and improvements in LVEF, left ventricular end‐diastolic inner‐dimension (LVIDd) and diastolic function (E/A and e/e′). While there was no difference in rates of hospitalization (for heart failure or overall), mortality was significantly lower in patients treated with SGLT2i compared with those who were not (6.5 vs. 16.6%, P = 0.049). Conclusions: We observed an improvement in mortality in patients undergoing CRT prescribed SGLT2i compared with those not prescribed SGLT2i, despite similar degrees of reverse remodelling. The authors recommend starting SGLT2i prior to CRT implantation, where it does not delay implantation. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic bronchitis, emphysema and vascular remodelling. The disease is associated with hypoxia, inflammation and oxidative stress. Lung fibroblasts are important cells in remodelling processes in COPD, as main producers of extracellular matrix proteins but also in synthesis of growth factors and inflammatory mediators. Methods: In this study we aimed to investigate if there are differences in how primary distal lung fibroblasts obtained from COPD patients and healthy subjects respond to hypoxia (1% O2) and pro-fibrotic stimuli with TGF-β1 (10 ng/mL). Genes and proteins associated with oxidative stress, endoplasmic reticulum stress, remodelling and inflammation were analysed with RT-qPCR and ELISA. Results: Hypoxia induced differences in expression of genes involved in oxidative stress (SOD3 and HIF-1α), ER stress (IRE1, PARK and ATF6), apoptosis (c-Jun and Bcl2) and remodelling (5HTR2B, Collagen7 and VEGFR2) in lung fibroblasts from COPD subjects compared to control subjects, where COPD fibroblasts were in general less responsive. The release of VEGF-C was increased after hypoxia, whereas TGF-β significantly reduced the VEGF response to hypoxia and the release of HGF. COPD fibroblasts had a higher release of IL-6, IL-8, MCP-1 and PGE2 compared to lung fibroblasts from control subjects. The release of inflammatory mediators was less affected by hypoxia, whereas TGFβ1 induced differences in inflammatory profile between fibroblasts from COPD and control subjects. Conclusion: These results suggest that there is an alteration of gene regulation of various stress responses and remodelling associated mediator release that is related to COPD and hypoxia, where fibroblasts from COPD patients have a deficient response. [ABSTRACT FROM AUTHOR]

Aims Atrial fibrillation (AF), the most common cardiac arrhythmia favouring ischemic stroke and heart failure involves left atrial remodelling, fibrosis and a complex interplay between cardiovascular risk factors. This study examined whether activated factor X (FXa) induces pro-remodelling and pro-fibrotic responses in atrial endothelial cells (AECs) and human atrial tissues and determined the underlying mechanisms. Methods and results AECs collected from porcine hearts and human right atrial appendages (RAA) from patients undergoing heart surgery. Protein expression levels were assessed by Western blot and immunofluorescence staining, mRNA levels by RT-qPCR, formation of reactive oxygen species (ROS) and NO using fluorescent probes, thrombin and angiotensin II generation by specific assays, fibrosis by Sirius red staining and senescence by senescence-associated beta-galactosidase (SA-β-gal) activity. In AECs, FXa increased ROS formation, senescence (SA-β-gal activity, p53, p21), angiotensin II generation and the expression of pro-inflammatory (VCAM-1, MCP-1), pro-thrombotic (tissue factor), pro-fibrotic (TGF-β and collagen-1/3a) and pro-remodelling (MMP-2/9) markers whereas eNOS levels and NO formation were reduced. These effects were prevented by inhibitors of FXa but not thrombin, protease-activated receptors antagonists (PAR-1/2) and inhibitors of NADPH oxidases, ACE, AT1R, SGLT1/SGLT2. FXa also increased expression levels of ACE1, AT1R, SGLT1/2 proteins which were prevented by SGLT1/2 inhibitors. Human RAA showed tissue factor mRNA levels that correlated with markers of endothelial activation, pro-remodelling and pro-fibrotic responses and SGLT1/2 mRNA levels. They also showed protein expression levels of ACE1, AT1R, p22phox, SGLT1/2, and immunofluorescence signals of nitrotyrosine and SGLT1/2 colocalized with those of CD31. FXa increased oxidative stress levels which were prevented by inhibitors of the AT1R/NADPH oxidases/SGLT1/2 pathway. Conclusion FXa promotes oxidative stress triggering premature endothelial senescence and dysfunction associated with pro-thrombotic, pro-remodelling and pro-fibrotic responses in AECs and human RAA involving the AT1R/NADPH oxidases/SGLT1/2 pro-oxidant pathway. Targeting this pathway may be of interest to prevent atrial remodelling and the progression of atrial fibrillation substrate. [ABSTRACT FROM AUTHOR]

Abstract Aims Cardiac dysfunction is commonly observed in patients with subarachnoid haemorrhage (SAH). However, the specific timeline of cardiac remodelling and the underlying mechanisms responsible for this effect following SAH remain unknown. This study aims to explore the impact of SAH on cardiac dysfunction and its potential mechanisms over time. Methods and results In Protocol 1, we investigated cardiac function and potential mechanisms in a Sprague‐Dawley rat model of SAH at six time points (baseline and Days 1, 3, 7, 14, and 28) while exploring the underlying mechanisms. Our assessments included the haemodynamic profile, echocardiography, and the concentrations of plasma biomarkers at various time points post‐SAH. We determined neuropeptide Y (NPY) 1–5 receptor protein expression levels through western blotting. In Protocol 2, we administered an NPY1 receptor antagonist to evaluate the effects of cardiac dysfunction induced by SAH on Day 3. In Protocol 1, SAH gradually provoked cardiac systolic dysfunction during the acute phase, reaching its peak on Day 3 without concurrent alterations in wall thickness. However, no significant changes were observed from Days 14 to 28 compared with Day 0. The changes in cardiac dysfunction were consistent with myocardial injury, inflammatory biomarkers, and NPY levels. SAH resulted in a heightened heart rate and systolic blood pressure, correlating with elevated epinephrine and norepinephrine levels. In Protocol 2, the administration of the NPY1 receptor antagonist effectively ameliorated cardiac dysfunction. Conclusions SAH induces transient cardiac dysfunction in the acute phase, and the underlying mechanisms for this response involve the NPY–NPY1 receptor pathway, otherwise known as catecholamines.

Background Over the past two decades, heart failure in children has increased in terms of symptom recognition and prevalence. The initial clinical manifestations of heart failure in children are non-specific. Therefore, diagnosis requires the support of echocardiography. The symptomatic severity of heart failure in children can be classified through a simple scoring system such as Ross score. The duration of heart disease, duration of therapy, and cardiac remodeling status may have clinical and anatomical effects on the disease. Objective To analyze for a possible correlation between modified Ross score and echocardiographic score by subgroup analysis consisting of duration of heart disease, duration of therapy, and cardiac remodeling. Methods This cross-sectional study included children aged 1 month - 18 years with heart failure who sought treatment at Prof.Dr. I.G.N.G Ngoerah Hospital, Denpasar from June 2019 to February 2020. Cardiac remodeling was defined as >20% increase in left ventricle internal end diastolic dimension (LVIDd) compared to normal values, ??based on body surface area. Spearman’s correlation test was used for statistical analysis. Results A total of 30 subjects were analyzed in this study. The median modified Ross score and echocardiography score were 3 points (range 2-11) and 4 (range 2-6), respectively. The median durations of heart disease and preventive heart failure therapy were 2 years (range 7 days-15 years) and 1 year (range 7 days-15 years), respectively. The mean LVIDd was 4.3 (SD 1.4) cm. Twenty-one out of 30 subjects experienced a ? 20% increase of LVIDd from baseline. The modified Ross score and echocardiographic score had no significant correlation (r=0.18; P=0.33). However, the modified Ross score had significant correlations with duration of heart disease (r=-0.632; P0.05). Echocardiography score and remodelling process was significantly correlated (r=0.64; P

Diabetes is a diverse metabolic disease that is caused by increased levels of blood glucose, which also leads to the generation of several other complications. The formation of wounds and their delayed healing are among the main areas of concern. Wound repair is a process, which replaces damaged cells with healthy cells; it generally occurs in four steps – haemostasis, inflammation, proliferation and remodelling. This review covers the causes of diabetes mellitus, its prevalence, its impact on wound healing, different types of wounds and their management. Diabetes mellitus impairs wound healing through several mechanisms such as impaired angiogenesis, altered collagen production, etc. [ABSTRACT FROM AUTHOR]

Recurrent wheezing in preschool children is heterogeneous and results from numerous genetic and environmental risk factors, which result in the same final clinical manifestation of acute episodes of wheezing but have distinct underlying mechanisms. Effective disease‐modifying approaches, therefore, need to target the pathways driving the symptoms. We have good evidence to show that targeting airway eosinophilia alone in early‐life preschool wheezing and using inhaled corticosteroids is not disease‐modifying. Although airway remodelling develops early in preschool wheezing, the challenge is identifying suitable treatments for structural airway changes. There is increasing evidence for the role of lower airway bacterial infection contributing to wheeze episodes, but clinical trials investigating the impact of targeted antibiotic treatment on disease modification are needed. There is also increasing data supporting an association between lower airway neutrophilia and wheezing in a subgroup of preschool children, but direct causation and the role of neutrophil function remain unknown. Finally, there is encouraging preliminary data for the role of inactivated mixed bacterial lysates in children with non‐allergic, infection‐associated wheeze episodes, but the impact on longer‐term outcomes and their mechanism of action is unknown. This review outlines a range of potential novel targets and approaches that may enable secondary prevention of asthma from preschool wheezing. In parallel, the potential for harm when interventions are introduced indiscriminately is highlighted. Some of the challenges that need to be addressed, including trial designs allowing tailored interventions, the need for non‐invasive biomarkers for targeted interventions, and ensuring extended and long‐term follow‐up after intervention, are highlighted. [ABSTRACT FROM AUTHOR]

There is a need to fully understand intra‐skeletal variability within different populations to develop and improve age‐at‐death estimation methods. This study evaluates age‐related histomorphometric changes in three different bones intra‐individually in a modern Australian sample. Four female and 13 male elderly Australian adult donors (67–93 years) were examined for osteon population density (OPD), osteon area (On.Ar), and Haversian canal area (H.Ar) of secondary osteons to compare between femora, ribs, and humeri and assess against age. In the pooled sex sample, no statistically significant correlations were observed between age and each histological variable. In the males, OPD of the femur increased significantly with age, as did porosity in the rib. In the male humeri, OPD increased moderately with age, while H.Ar was decreased moderately with age. Intra‐bone comparisons showed that males had significantly higher osteon counts in their ribs compared to their femora, while their ribs showed statistically significantly less porosity than their humeri. When bone size was accounted for, by adjusting the femur and humerus histology data by robusticity indices, histology values were found to be similar between bones within the same individual. This is despite the upper and lower limbs receiving different ranges and types of biomechanical load. Our findings demonstrate that bone size influences histomorphometry, and this could confound age‐at‐death estimations that have not been adjusted for robusticity. Future studies would benefit from examining bone histomorphometry within a larger sample size and incorporating bone robusticity measures into histology analyses. [ABSTRACT FROM AUTHOR]

Aims: Cardiac dysfunction is commonly observed in patients with subarachnoid haemorrhage (SAH). However, the specific timeline of cardiac remodelling and the underlying mechanisms responsible for this effect following SAH remain unknown. This study aims to explore the impact of SAH on cardiac dysfunction and its potential mechanisms over time. Methods and results: In Protocol 1, we investigated cardiac function and potential mechanisms in a Sprague‐Dawley rat model of SAH at six time points (baseline and Days 1, 3, 7, 14, and 28) while exploring the underlying mechanisms. Our assessments included the haemodynamic profile, echocardiography, and the concentrations of plasma biomarkers at various time points post‐SAH. We determined neuropeptide Y (NPY) 1–5 receptor protein expression levels through western blotting. In Protocol 2, we administered an NPY1 receptor antagonist to evaluate the effects of cardiac dysfunction induced by SAH on Day 3. In Protocol 1, SAH gradually provoked cardiac systolic dysfunction during the acute phase, reaching its peak on Day 3 without concurrent alterations in wall thickness. However, no significant changes were observed from Days 14 to 28 compared with Day 0. The changes in cardiac dysfunction were consistent with myocardial injury, inflammatory biomarkers, and NPY levels. SAH resulted in a heightened heart rate and systolic blood pressure, correlating with elevated epinephrine and norepinephrine levels. In Protocol 2, the administration of the NPY1 receptor antagonist effectively ameliorated cardiac dysfunction. Conclusions: SAH induces transient cardiac dysfunction in the acute phase, and the underlying mechanisms for this response involve the NPY–NPY1 receptor pathway, otherwise known as catecholamines. [ABSTRACT FROM AUTHOR]

Aims To assess the agreement between left ventricular end-diastolic diameter index (LVEDDi) and volume index (LVEDVi) to define LV dilatation and to investigate the respective prognostic implications in patients with heart failure (HF). Methods and results Patients with HF symptoms and LV ejection fraction (LVEF) < 50% undergoing cardiac magnetic resonance were evaluated retrospectively. LV dilatation was defined as LVEDDi or LVEDVi above the upper normal limit according to published reference values. Patients were followed up for the combined endpoint of cardiovascular death or HF hospitalization during 5 years. A total of 564 patients (median age 64 years; 79% men) were included. LVEDDi had a modest correlation with LVEDVi (r = 0.682, P < 0.001). LV dilatation was noted in 84% of patients using LVEDVi-based definition and in 73% using LVEDDi-based definition, whereas 20% of patients displayed discordant definitions of LV dilatation. During a median follow-up of 2.8 years, patients with both dilated LVEDDi and LVEDVi had the highest cumulative event rate (HR 3.00, 95% CI 1.15–7.81, P = 0.024). Both LVEDDi and LVEDVi were independently associated with the primary outcome (hazard ratio 3.29, 95%, P < 0.001 and 2.8, P = 0.009; respectively). Conclusion The majority of patients with HF and LVEF < 50% present both increased LVEDDi and LVEDVi whereas 20% show discordant linear and volumetric definitions of LV dilatation. Patients with increased LVEDDi and LVEDVi have the worst clinical outcomes suggesting that the assessment of these two metrics is needed for better risk stratification. [ABSTRACT FROM AUTHOR]

Aims Following myocardial infarction (MI), the heart repairs itself via a fibrotic repair response. The degree of fibrosis is determined by the balance between deposition of extracellular matrix (ECM) by activated fibroblasts and breakdown of nascent scar tissue by proteases that are secreted predominantly by inflammatory cells. Excessive proteolytic activity and matrix turnover has been observed in human heart failure, and protease inhibitors in the injured heart regulate matrix breakdown. Serine protease inhibitors (Serpins) represent the largest and the most functionally diverse family of evolutionary conserved protease inhibitors, and levels of the specific Serpin, SerpinA3, have been strongly associated with clinical outcomes in human MI as well as non-ischaemic cardiomyopathies. Yet, the role of Serpins in regulating cardiac remodelling is poorly understood. The aim of this study was to understand the role of Serpins in regulating scar formation after MI. Methods and results Using a SerpinA3n conditional knockout mice model, we observed the robust expression of Serpins in the infarcted murine heart and demonstrate that genetic deletion of SerpinA3n (mouse homologue of SerpinA3) leads to increased activity of substrate proteases, poorly compacted matrix, and significantly worse post-infarct cardiac function. Single-cell transcriptomics complemented with histology in SerpinA3n-deficient animals demonstrated increased inflammation, adverse myocyte hypertrophy, and expression of pro-hypertrophic genes. Proteomic analysis of scar tissue demonstrated decreased cross-linking of ECM peptides consistent with increased proteolysis in SerpinA3n-deficient animals. Conclusion Our study demonstrates a hitherto unappreciated causal role of Serpins in regulating matrix function and post-infarct cardiac remodelling. [ABSTRACT FROM AUTHOR]

Background Over the past two decades, heart failure in children has increased in terms of symptom recognition and prevalence. The initial clinical manifestations of heart failure in children are non-specific. Therefore, diagnosis requires the support of echocardiography. The severity of heart failure symptom in children can be classified through a simple scoring system such as Ross score. The cardiac remodeling status, duration of heart disease and treatment may have clinical and anatomical effects on the disease. Objective To analyze correlation between modified Ross score and echocardiographic score by subgroup analysis consisting of cardiac remodeling status, duration of heart disease and treatment. Methods This cross-sectional study included children aged 1 month to 18-years-old with heart failure who sought treatment at Prof.Dr. I.G.N.G Ngoerah Hospital, Denpasar from June 2019 to February 2020. Cardiac remodeling was defined as >20% increase in left ventricle internal end diastolic dimension (LVIDd) compared to normal values, based on body surface area. Spearman's correlation test was used for statistical analysis. Results A total of 30 subjects were analyzed in this study. The median modified Ross score and echocardiography score were 3 (range 2-11) points and 4 (range 2-6) points, respectively. The median durations of heart disease and preventive heart failure treatment were 2 years (range 7 days-15 years) and 1 year (range 7 days-15 years), respectively. The mean LVIDd was 4.3 (SD 1.4) cm. Twenty-one out of 30 subjects experienced a ≥ 20% increase of LVIDd from baseline. The modified Ross score and echocardiographic score had no significant correlation (r=0.18; P=0.33). However, the modified Ross score had significant correlations with duration of heart disease (r=-0.632; P<0.001) as well as duration of treatment (r=-0.584; P=0.001). In addition, no correlation was found between echocardiographic score with heart disease and treatment duration (P>0.05). Echocardiography score and remodeling process was significantly correlated (r=0.64; P<0.001). Conclusion There is no correlation between modified Ross score and echocardiographic score. Duration of heart disease and treatment are significantly negatively correlated with modified Ross scores. The remodeling process is positively correlated with echocardiographic score. Further research on acute heart failure and validated echocardiographic scores are needed. [ABSTRACT FROM AUTHOR]

A two-stage model is proposed for investigating remodelling characteristics in bone over time and distance to the growth plate. The first stage comprises a partial differential equation (PDE) for bone density as a function of time and distance from the growth plate. This stage clarifies the contributions to changes in bone density due to remodelling and growth processes and tracks the rate at which new bone emanates from the growth plate. The second stage consists of simulating the remodelling process to determine remodelling characteristics. Implementing the second stage requires the rate at which bone moves away from the growth plate computed during the first stage. The second stage is also needed to confirm that remodelling characteristics predicted by the first stage may be explained by a realistic model for remodelling and to compute activation frequency. The model is demonstrated on microCT scans of tibia of juvenile female rats in three experimental groups: sham-operated control, oestrogen deprived, and oestrogen deprived followed by treatment. Model predictions for changes in bone density and remodelling characteristics agree with the literature. In addition, the model provides new insight into the role of treatment on the density of new bone emanating from the growth plate and provides quantitative descriptions of changes in remodelling characteristics beyond what has been possible to ascertain by experimentation alone. [ABSTRACT FROM AUTHOR]

As the biological mechanisms of orthodontic tooth movement have been explored further, scholars have gradually focused on the remodelling mechanism of the extracellular matrix (ECM) in the periodontal ligament (PDL). The ECM of the PDL consists of various types of collagens and other glycoproteins. The specific process and mechanism of ECM remodelling during orthodontic tooth movement remains unclear. Collagen I and III, which constitute major components of the PDL, are upregulated under orthodontic force. The changes in the contents of ECM proteins also depend on the expression of ECM-related enzymes, which organise new collagen fibre networks to adapt to changes in tooth position. The matrix metalloproteinase family is the main enzyme that participates in collagen hydrolysis and renewal and changes its expression under orthodontic force. Moreover, ECM adhesion molecules, such as integrins, are also regulated by orthodontic force and participate in the dynamic reaction of cell adhesion and separation with the ECM. This article reviews the changes in ECM components, related enzymes and adhesion molecules in the PDL under orthodontic force to lay the foundation for the exploration of the regulatory mechanism of ECM remodelling during orthodontic tooth movement. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction in cardiomyocytes is a hallmark of heart failure development. Although initial studies recognized the importance of different mitochondrial subpopulations, there is a striking lack of direct comparison of intrafibrillar (IF) versus perinuclear (PN) mitochondria during the development of HF. Here, we use multiple approaches to examine the morphology and functional properties of IF versus PN mitochondria in pressure overload-induced cardiac remodelling in mice, and in non-failing and failing human cardiomyocytes. We demonstrate that PN mitochondria from failing cardiomyocytes are more susceptible to depolarization of mitochondrial membrane potential, reactive oxygen species generation and impairment in Ca2+ uptake compared with IF mitochondria at baseline and under physiological stress protocol. We also demonstrate, for the first time to our knowledge, that under normal conditions PN mitochondrial Ca2+ uptake shapes nucleoplasmic Ca2+ transients (CaTs) and limits nucleoplasmic Ca2+ loading. The loss of PN mitochondrial Ca2+ buffering capacity translates into increased nucleoplasmic CaTs and may explain disproportionate rise in nucleoplasmic [Ca2+] in failing cardiomyocytes at increased stimulation frequencies. Therefore, a previously unidentified benefit of restoring the mitochondrial Ca2+ uptake may be normalization of nuclear Ca2+ signalling and alleviation of altered excitation-transcription, which could be an important therapeutic approach to prevent adverse cardiac remodelling. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.

Abstract Background In Sweden, most children with slipped capital femoral epiphysis (SCFE) are operated on with a single smooth pin or a short-threaded screw, allowing further growth of the femoral neck. Using the Swedish Pediatric Orthopaedic Quality registry, SPOQ, we investigated whether angular remodelling occurs adjacent to the proximal femoral epiphysis after fixation of SCFE using implants, allowing continued growth of the femoral neck. Methods During 2008–2010 a total national population of 155 children were reported to the SPOQ registry. Following our strict inclusion criteria, radiographs of 51 hips were further assessed. The lateral Head Shaft Angle (HSA), the Nötzli 3-point α-angle, the anatomic α-angle, and the Anterior Offset Ratio (AOR) on the first postoperative radiographs and at follow-up were measured to describe the occurrence of remodelling. Slip severity was categorised as mild, moderate or severe according to postoperative HSA. Results Mean and SD values for the change in HSA were 3,7° (5,0°), for 3-point α-angle 6,8° (8,9°), and anatomic α-angle 13,0° (16,3°). The overall increase in AOR was 0,038 (0.069). There were no significant differences between the slip severity groups. Conclusions We found limited angular remodelling after in situ fixation with smooth pins or short threaded screws for SCFE. The angular remodelling and the reduction of the CAM deformity was less than previously described after fixation of SCFE with similar implants. Results about the same magnitude with non-growth sparing techniques suggest that factors other than longitudinal growth of the femoral neck are important for angular remodelling.

Background and Objectives: Left atrial (LA) remodelling and dilatation predicts atrial fibrillation (AF) recurrences after catheter ablation. However, whether right atrial (RA) remodelling and dilatation predicts AF recurrences after ablation has not been fully evaluated. Materials and Methods: This is an observational study of 85 consecutive patients (aged 57 ± 9 years; 70 [82%] men) who underwent cardiac magnetic resonance before first catheter ablation for AF (40 [47.1%] persistent AF). Four-chamber cine-sequence was selected to measure LA and RA area, and ventricular end-systolic image phase to obtain atrial 3D volumes. The effect of different variables on event-free survival was investigated using the Cox proportional hazards model. Results: In patients with persistent AF, combined LA and RA area indexed to body surface area (AILA + RA) predicted AF recurrences (HR = 1.08, 95% CI 1.00–1.17, p = 0.048). An AILA + RA cut-off value of 26.7 cm2/m2 had 72% sensitivity and 73% specificity for predicting recurrences in patients with persistent AF. In this group, 65% of patients with AILA + RA > 26.7 cm2/m2 experienced AF recurrence within 2 years of follow-up (median follow-up 11 months), compared to 25% of patients with AILA + RA ≤ 26.7 cm2/m2 (HR 4.28, 95% CI 1.50–12.22; p = 0.007). Indices of LA and RA dilatation did not predict AF recurrences in patients with paroxysmal AF. Atrial 3D volumes did not predict AF recurrences after ablation. Conclusions: In this pilot study, the simple measurement of AILA + RA may predict recurrences after ablation of persistent AF, and may outperform measurements of atrial volumes. In paroxysmal AF, atrial dilatation did not predict recurrences. Further studies on the role of RA and LA remodelling are needed. [ABSTRACT FROM AUTHOR]

This essay will discuss the evolution of writings about adaptive reuse. The architectural practice is as old as the buildings themselves, yet it has scarcely been discussed or even recognised until relatively recently. The essay will document the varied influences that informed the early publications (the first from 1976). The lack of easily available material (that is, books and documented buildings) meant that pioneering writers had to draw upon other sources—those beyond established architectural discussions. Therefore, these early authors were not limited by the strictures of an already established subject but were able to collate information from a variety of sources. Thus, adaptive reuse draws upon a collage of different sources, many beyond pure architecture, including installation art, fine art, curation, interior design, and urban design. Inevitably, as the subject moves from the periphery of architectural practice towards the middle ground, the number of publications has increased. This diversity has provided the subject with a greater scope, supporting the acknowledgement of the importance of technology, sustainability, and conservation in addition to ideas of heritage and culture, while also allowing for a much less Western-centric focus.

Abstract Background Salivary carcinoma ex pleomorphic adenoma (CXPA) is defined as a carcinoma that develops from benign pleomorphic adenoma (PA). Abnormally activated Androgen signaling pathway and amplification of HER-2/neu(ERBB-2) gene are known to be involved in CXPA tumorigenesis. Recent progress in tumour microenvironment research has led to identification that extracellular matrix (ECM) remodelling and increased stiffness act as critical contributing role in tumour carcinogenesis. This study examined ECM modifications to elucidate the mechanism underlying CXPA tumorigenesis. Results PA and CXPA organoids were successfully established. Histological observation, immunohistochemistry (IHC), and whole-exome sequencing demonstrated that organoids recapitulated phenotypic and molecular characteristics of their parental tumours. RNA-sequencing and bioinformatic analysis of organoids showed that differentially expressed genes are highly enriched in ECM-associated terms, implying that ECM alternations may be involved in carcinogenesis. Microscopical examination for surgical samples revealed that excessive hyalinized tissues were deposited in tumour during CXPA tumorigenesis. Transmission electron microscopy confirmed that these hyalinized tissues were tumour ECM in nature. Subsequently, examination by picrosirius red staining, liquid chromatography with tandem mass spectrometry, and cross-linking analysis indicated that tumour ECM was predominantly composed of type I collagen fibers, with dense collagen alignment and an increased level of collagen cross-linking. IHC revealed the overexpression of COL1A1 protein and collagen-synthesis-related genes, DCN and IGFBP5 (p

Laser‐assisted drug delivery (LADD) is a treatment method to enhance the penetration of pharmaceuticals through the skin. The aim of the present study is to track hyaluronic acid (HA) and analyse its effect on human skin in vivo after ablative fractional laser (AFL) treatment. Healthy male and female subjects were recruited. Four areas were marked on their forearms of each volunteer, and each area was assigned to one of the following treatment options: AFL + HA, AFL only, HA only or untreated control. A carbon dioxide laser was used for the AFL treatment. Follow‐up measurements were scheduled 30 min and 30 days after treatment using multiphoton tomography equipped with fluorescence lifetime imaging (MPT‐FLIM). A total of 11 subjects completed the study. By detecting fluorescence lifetimes, the HA and the anaesthetic ointment were clearly distinguishable from surrounding tissue. After AFL treatment, HA could be visualized in all epidermal and upper dermal layers. In contrast, HA in intact skin was only detected in the superficial layers at distinctly lower levels. The applied HA gel seemed to have beneficial properties for the wound healing process after laser treatment. LADD has proven to be a fast and effective method to increase HA uptake into the skin, allowing for improved hydration and skin rejuvenation over time. Furthermore, LADD could be a beneficial treatment option in laser resurfacing. MPT‐FLIM proved to be an appropriate diagnostic tool for drug delivery tracking and monitoring of treatment response for individualized therapy adjustment. [ABSTRACT FROM AUTHOR]

In a physiological context, the extracellular matrix (ECM) provides an important scaffold for organs. Dysregulation of ECM in disease conditions, characterised by excess deposition of connective tissue and extracellular matrix in response to a pathological insult, is a key driver of disease progression in multiple organs. The resultant fibrosis is predominantly an irreversible process and directly contributes to, and exacerbates, dysfunction of an affected organ. This is particularly paramount in the kidney, liver, heart and lung. A hybrid Joint Meeting of NC‐IUPHAR and British Pharmacological Society was held in Paris and via a webinar in November 2020, when two successive sessions were devoted to translational advances in fibrosis as a therapeutic target. On the upsurge of response to these sessions, the concept of a special themed issue on this topic emerged, and is entitled Translational Advances in Fibrosis as a Therapeutic Target. In this special issue, we seek to provide an up‐to‐date account of the diverse molecular mechanisms and causal role that fibrosis plays in disease progression (contributing to, and exacerbating, dysfunction of affected organs). Recent developments in the understanding of molecular targets involved in fibrosis, and how their actions can be manipulated therapeutically, are included. LINKED ARTICLES: This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc [ABSTRACT FROM AUTHOR]

Purpose: Foot adaptation in the typically developed foot is well explored. In this study, we aimed to explore the form and function of an atypical foot, the Chinese bound foot, which had a history of over a thousand years but is not practised anymore. Methods: We evaluated the foot shape and posture via a statistical shape modelling analysis, gait plantar loading distribution via gait analysis, and bone density adaptation via implementing finite element simulation and bone remodelling prediction. Results: The atypical foot with binding practice led to increased foot arch and vertically oriented calcaneus with larger size at the articulation, apart from smaller metatarsals compared with a typically developed foot. This shape change causes the tibia, which typically acts as a load transfer beam and shock absorber, to extend its function all the way through the talus to the calcaneus. This is evident in the bound foot by i) the reduced center of pressure trajectory in the medial–lateral direction, suggesting a reduced supination–pronation; ii) the increased density and stress in the talus–calcaneus articulation; and iii) the increased bone growth in the bound foot at articulation joints in the tibia, talus, and calcaneus. Conclusion: Knowledge from the last-generation bound foot cases may provide insights into the understanding of bone resorption and adaptation in response to different loading profiles. [ABSTRACT FROM AUTHOR]

Forearm and wrist fractures are the most common fractures in children. Compared with adults, children have different fracture patterns, and their bones have better remodelling potential. Despite the frequency of injuries, until recently there has been little evidence to guide treatment, with considerable variation in practice. The "British Orthopaedic Association Standard for Trauma (BOAST): Early Management of Paediatric Forearm Fractures" has provided the orthopaedic community with coherent standards for management of angulated but not off-ended fractures. However, there are areas that still cause controversy among clinicians. This article aims to simplify the topic by providing junior trainees with an up-to-date overview of classifications, assessment, and management options for paediatric forearm fractures. [ABSTRACT FROM AUTHOR]

COVID-19 brought travel as we know it to a complete standstill. At the time it was believed that the impact of the pandemic was unprecedented and that the projected recovery would need to be both different and transformative. This was particularly evident from a product (supply) point of view given the renewed attempts to increase tourists (demand) to destinations. As a result of this hiatus, the travel industry needed to reconsider the shape and form of the tourism product in order to revive and ensure its sustainability. The objective of this investigation is to demonstrate how the product (supply) could be remodelled in a destabilised environment as a contingency plan so as to maintain and sustain tourist arrivals (demand) in the wake of any internal crises and other external emergencies. As a result, this article presents research on a newly devised novel approach to remodel the actual supply-side of the domestic tourism value chain so as to become more resilient and resistant. In principle this remodelling hones in on stimulating the development of a tourism product that takes into account other dimensions that were not formerly or conventionally regarded as part of the hyper-local touristic experience. [ABSTRACT FROM AUTHOR]

Background: Periodontitis is an inflammatory disease of the teeth-supporting tissues caused by microorganisms. Robusta coffee bean extract has antibacterial properties due to its caffeine, flavonoids, trigonelline, and chlorogenic acid contents. The robusta coffee bean extract also regulates alveolar bone healing through bone remodelling. Aim: The study aimed to investigate robusta coffee bean extract to inhibit bacterial growth and accelerate bone repair in vitro and in vivo. Methods: This study used the paper disc diffusion method with the research group of robusta coffee bean extract with concentrations of 50%, 25%, 12.5%, 6.25%, and negative control, as much as 20 and dripped onto the disc paper then placed on the surface of the agar media that had been inoculated with bacteria. The diameter of the inhibition zone was measured. Twenty periodontitis rat models were given 0.05 ml of the robusta coffee bean extract on the molars and put in a periodontal pocket for seven days. Rats were decapitated, and alveolar bone tissues were stained with HE and IHC staining. The number of osteoclasts, osteoblasts and BMP-2 was counted using a microscope. Statistical test with Kruskal Wallis followed by Mann Whitney showed a p-value of

Abstract Aims Sacubitril/valsartan has changed the treatment of heart failure with reduced ejection fraction (HFrEF), due to the positive effects on morbidity and mortality, partly mediated by left ventricular (LV) reverse remodelling (LVRR). The aim of this multicenter study was to identify echocardiographic predictors of LVRR after sacubitril/valsartan administration. Methods and results Patients with HFrEF requiring therapy with sacubitril/valsartan from 13 Italian centres were included. Echocardiographic parameters including LV global longitudinal strain (GLS) and global peak atrial longitudinal strain by speckle tracking echocardiography were measured to find the predictors of LVRR [= LV end‐systolic volume reduction ≥10% and ejection fraction (LVEF) improvement ≥10% at follow‐up] at 6 month follow‐up as the primary endpoint. Changes in symptoms [New York Heart Association (NYHA) class] and neurohormonal activations [N‐terminal pro‐brain natriuretic peptide (NT‐proBNP)] were also evaluated as secondary endpoints; 341 patients (excluding patients with poor acoustic windows and missing data) were analysed (mean age: 65 ± 10 years; 18% female, median LVEF 30% [inter‐quartile range: 25−34]). At 6 month follow‐up, 82 (24%) patients showed early complete response (LVRR and LVEF ≥ 35%), 55 (16%) early incomplete response (LVRR and LVEF

In the last decade, e-cigarette usage has increased, with an estimated 82 million e-cigarette users globally. This is, in part, due to the common opinion that they are "healthier" than tobacco cigarettes or simply "water vapour". Third-hand e-vapour exposure is the chemical residue left behind from e-cigarette aerosols, which is of concern due to its invisible nature, especially among young children. However, there is limited information surrounding third-hand e-vapour exposure. This study aimed to investigate the pulmonary effects of sub-chronic third-hand e-vapour exposure in a murine model. BALB/c mice (4 weeks of age) were exposed to a towel containing nicotine free (0 mg) e-vapour, nicotine (18 mg) e-vapour, or no e-vapour (sham) and replaced daily for 4 weeks. At the endpoint, lung function was assessed, and bronchoalveolar lavage fluid and lungs were collected to measure inflammation and fibrosis. Mice exposed to third-hand e-vapour without nicotine had alveolar enlargement compared to sham exposed controls. Mice exposed to third-hand e-vapour with nicotine had reduced bronchial responsiveness to provocation, increased epithelial thickening in large airways, increased epithelial layers in small airways, alveolar enlargement, and increased small airway collagen deposition, compared to sham exposed controls. In conclusion, our study shows that third-hand e-vapour exposure, particularly in the presence of nicotine, negatively affects the lung health of mice and highlights the need for greater public awareness surrounding the dangers of third-hand exposure to e-cigarette vapour. [ABSTRACT FROM AUTHOR]

This essay will discuss the evolution of writings about adaptive reuse. The architectural practice is as old as the buildings themselves, yet it has scarcely been discussed or even recognised until relatively recently. The essay will document the varied influences that informed the early publications (the first from 1976). The lack of easily available material (that is, books and documented buildings) meant that pioneering writers had to draw upon other sources—those beyond established architectural discussions. Therefore, these early authors were not limited by the strictures of an already established subject but were able to collate information from a variety of sources. Thus, adaptive reuse draws upon a collage of different sources, many beyond pure architecture, including installation art, fine art, curation, interior design, and urban design. Inevitably, as the subject moves from the periphery of architectural practice towards the middle ground, the number of publications has increased. This diversity has provided the subject with a greater scope, supporting the acknowledgement of the importance of technology, sustainability, and conservation in addition to ideas of heritage and culture, while also allowing for a much less Western-centric focus. [ABSTRACT FROM AUTHOR]

Aims: Dapagliflozin improves the prognosis of patients with heart failure (HF), regardless of left ventricular ejection fraction (LVEF). However, its effect on cardiac remodelling parameters, specifically left atrial (LA) remodelling, is not well established. Methods and results: The DAPA‐MODA trial (NCT04707352) is a multicentre, single‐arm, open‐label, prospective and interventional study that aimed to evaluate the effect of dapagliflozin on cardiac remodelling parameters over 6 months. Patients with stable chronic HF receiving optimized guideline‐directed therapy, except for any sodium–glucose cotransporter 2 inhibitor, were included. Echocardiography was performed at baseline, 30 and 180 days, and analysed by a central core‐lab in a blinded manner to both patient and time. The primary endpoint was the change in maximal LA volume index (LAVI). A total of 162 patients (64.2% men, 70.5 ± 10.6 years, 52% LVEF >40%) were included in the study. At baseline, LA dilatation was observed (LAVI 48.1 ± 22.6 ml/m2) and LA parameters were similar between LVEF‐based phenotypes (≤40% vs. >40%). LAVI showed a significant reduction at 180 days (−6.6% [95% confidence interval −11.1, −1.8], p = 0.008), primarily due to a decrease in reservoir volume (−13.8% [95% confidence interval −22.5, −4], p = 0.007). Left ventricular geometry improved with significant reductions in left ventricular mass index (−13.9% [95% confidence interval −18.7, −8.7], p < 0.001), end‐diastolic volume (−8.0% [95% confidence interval −11.6, −4.2], p < 0.001) and end‐systolic volume (−11.9% [95% confidence interval −16.7, −6.8], p < 0.001) at 180 days. N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) showed a significant reduction at 180 days (−18.2% [95% confidence interval −27.1, −8.2], p < 0.001), without changes in filling Doppler measures. Conclusion: Dapagliflozin administration in stable out‐setting patients with chronic HF and optimized therapy results in global reverse remodelling of cardiac structure, including reductions in LA volumes and improvement in left ventricular geometry and NT‐proBNP concentrations. [ABSTRACT FROM AUTHOR]

Aims Heart failure (HF) after myocardial infarction (MI) is a major cause of morbidity and mortality. We sought to investigate the functional importance of cardiac iron status after MI and the potential of pre-emptive iron supplementation in preventing cardiac iron deficiency (ID) and attenuating left ventricular (LV) remodelling. Methods and results MI was induced in C57BL/6J male mice by left anterior descending coronary artery ligation. Cardiac iron status in the non-infarcted LV myocardium was dynamically regulated after MI: non-haem iron and ferritin increased at 4 weeks but decreased at 24 weeks after MI. Cardiac ID at 24 weeks was associated with reduced expression of iron-dependent electron transport chain (ETC) Complex I compared with sham-operated mice. Hepcidin expression in the non-infarcted LV myocardium was elevated at 4 weeks and suppressed at 24 weeks. Hepcidin suppression at 24 weeks was accompanied by more abundant expression of membrane-localized ferroportin, the iron exporter, in the non-infarcted LV myocardium. Notably, similarly dysregulated iron homeostasis was observed in LV myocardium from failing human hearts, which displayed lower iron content, reduced hepcidin expression, and increased membrane-bound ferroportin. Injecting ferric carboxymaltose (15 µg/g body weight) intravenously at 12, 16, and 20 weeks after MI preserved cardiac iron content and attenuated LV remodelling and dysfunction at 24 weeks compared with saline-injected mice. Conclusion We demonstrate, for the first time, that dynamic changes in cardiac iron status after MI are associated with local hepcidin suppression, leading to cardiac ID long term after MI. Pre-emptive iron supplementation maintained cardiac iron content and attenuated adverse remodelling after MI. Our results identify the spontaneous development of cardiac ID as a novel disease mechanism and therapeutic target in post-infarction LV remodelling and HF. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common atrial tachyarrhythmia. One of the methods of AF treatment is direct current cardioversion (DCCV), but in the long-term follow-up we observe quite a high percentage of AF recurrences after this procedure. In order to assess the prognosis of DCCV effectiveness, we use clinical, biochemical and echocardiographic parameters. The objective of this review is to systematise the current knowledge on echocardiographic measurements in patients with persistent AF used to assess the progress of remodelling of the atrial wall, which affects the likelihood of maintaining sinus rhythm after DCCV. In this article, echocardiographic parameters for the evaluation of remodelling of the atrial wall are divided into groups referring to structural, mechanical, and electrical remodelling, as well as parameters for the evaluation of left ventricular filling pressure. The article aims to draw attention to the clinical value of echocardiographic measurements, which is the selection of patients who will maintain sinus rhythm after DCCV in the long-term follow-up, which will allow to avoid unnecessary risks associated with the procedure and enable the selection of the appropriate treatment strategy. [ABSTRACT FROM AUTHOR]

Epithelial-to-mesenchymal transition (EMT) is a reversible process, in which epithelial cells lose their epithelial traits and acquire a mesenchymal phenotype. This transformation has been described in different lung diseases, such as lung cancer, interstitial lung diseases, asthma, chronic obstructive pulmonary disease and other muco-obstructive lung diseases, such as cystic fibrosis and non-cystic fibrosis bronchiectasis. The exaggerated chronic inflammation typical of these pulmonary diseases can induce molecular reprogramming with subsequent self-sustaining aberrant and excessive profibrotic tissue repair. Over time this process leads to structural changes with progressive organ dysfunction and lung function impairment. Although having common signalling pathways, specific triggers and regulation mechanisms might be present in each disease. This review aims to describe the various mechanisms associated with fibrotic changes and airway remodelling involved in chronic airway diseases. Having better knowledge of the mechanisms underlying the EMT process may help us to identify specific targets and thus lead to the development of novel therapeutic strategies to prevent or limit the onset of irreversible structural changes. [ABSTRACT FROM AUTHOR]