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Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) hypertrophy, LV outflow tract obstruction, and left atrial dilation, which can be associated with progressive heart failure, atrial fibrillation, and stroke. Aficamten is a next-in-class cardiac myosin inhibitor that reduces outflow tract obstruction by modulating cardiac contractility, with the potential to reverse pathological remodeling and, in turn, reduce cardiovascular events. This study sought to investigate the effect of aficamten on cardiac remodeling compared with placebo using cardiovascular magnetic resonance (CMR) and its association with key clinical endpoints in the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) CMR substudy. SEQUOIA-HCM was a phase 3 double-blind, placebo-controlled trial for adults with symptomatic oHCM who were randomized 1:1 to 24 weeks of aficamten (dose range: 5-20 mg) or placebo. Eligible participants were offered enrollment in the CMR substudy with studies performed at baseline and week 24. Image analysis was performed in a blinded fashion by a core laboratory. Of the 282 randomized patients, 57 (20%) participated in the substudy, and of those, 50 (88%) completed both baseline and week 24 CMR. Baseline characteristics of the CMR cohort were similar to the overall study population. Of these 50 patients, 21 received aficamten and 29 received placebo. Relative to placebo, patients receiving aficamten demonstrated significant reductions (Δ least-squares mean) in LV mass index (−15 g/m2; 95% CI: −25 to −6 g/m2; P = 0.001), maximal LV wall thickness (−2.1 mm; 95% CI: −3.1 to −1.1 mm; P < 0.001), left atrial volume index (−13 mL/m2; 95% CI: −19 to −7 mL/m2; P < 0.001), native T1 relaxation time (−37 ms; 95% CI: −69 to −5 ms; P = 0.026), indexed extracellular volume fraction (−3.9 g/m2; 95% CI: −7.0 to −0.9 g/m2; P = 0.014), and indexed myocyte mass (−14 g/m2; 95% CI: −23 to −4 g/m2; P = 0.004), while there were no significant changes in LV chamber volumes, LV replacement fibrosis (late gadolinium enhancement mass −0.7 g; 95% CI: −2.9 to 1.6 g; P = 0.54), or extracellular volume (0.7%; 95% CI: −2.2% to 3.6%; P = 0.61). The CMR substudy of SEQUOIA-HCM demonstrated that treatment with aficamten relative to placebo for 24 weeks resulted in favorable cardiac remodeling. These changes, particularly with regard to LV mass, wall thickness, and left atrial size, could potentially lead to reduced cardiovascular events including heart failure and atrial fibrillation with longer follow-up. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818) [ABSTRACT FROM AUTHOR]

We employ the theory of asymptotic homogenization (AH) to study the elasto‐plastic behavior of a composite medium comprising two solid phases, separated by a sharp interface and characterized by mechanical properties, such as elastic coefficients and “initial yield stresses” (i.e., a threshold stress above which remodeling is triggered), that may differ up to several orders of magnitude. We speak of “plastic” behavior because we have in mind a material behavior that, to a certain extent, resembles plasticity, although, for biological systems, it embraces a much wider class of inelastic phenomena. In particular, we are interested in studying the influence of gradient effects in the remodeling variable on the homogenized mechanical properties of the composite. The jump of the mechanical properties from one phase to the other makes the composite highly heterogeneous and calls for the determination of effective properties, that is, properties that are associated with a homogenized “version” of the original composite, and that are obtained through a suitable averaging procedure. The determination of the effective properties results convenient, in particular, when it comes to the multiscale description of inelastic processes, such as remodeling in soft or hard tissues, like bones. To accomplish this task with the aid of AH, we assume that the length scale over which the heterogeneities manifest themselves is several orders of magnitude smaller than the characteristic length scale of the composite as a whole. We identify both a fine‐scale problem and a coarse‐scale problem, each of which characterizes the elasto‐plastic dynamics of the composite at the corresponding scale, and we discuss how they are reciprocally coupled through a transfer of information from one scale to the other. In particular, we highlight how the coarse‐scale plastic distortions influence the fine‐scale problem. Moreover, in the limit of negligible hysteresis effects, we individuate two viscoplastic effective coefficients that encode the information of the two‐scale nature of the composite medium in the upscaled equations. Finally, to deal with a case study tractable semi‐analytically, we consider a multilayered composite material with an initial yield stress that is constant in each phase. Such investigation is meant to contribute to the constitution of a robust framework for devising the effective properties of hierarchical biological media. [ABSTRACT FROM AUTHOR]

Background/Objective: Sensitization to specific IgE Staphylococcus aureus enterotoxins (SEs) is associated with an increased risk for severe asthma development. Limited data exist regarding the association of seropositivity for specific IgE SEs and the different aspects of severe asthma. We aimed to determine whether the presence of SEs is associated with asthma-related parameters such as inflammatory cells in the airways, features of airway remodeling, and other variables relating to asthma assessment and severity. Methods: Fifty patients with severe asthma were recruited in the study. Demographics, comorbidities, asthma duration, and asthma medication were recorded by treating physicians. Specific IgE SE measurement, lung function, atopic status, asthma control test (ACT), sputum induction, bronchoscopy with BAL, and indices of airway remodeling were also assessed. Results: Twelve patients were positive to enterotoxin sensitization. Patients seropositive to specific IgE SEs significantly differed in regard to FEV1% pred and FEV1/FVC ratio compared to seronegative ones. Analyzing the inflammatory variables obtained from induced sputum, BAL, and endobronchial biopsies, the only significant difference was that of smooth muscle area (SMA), which was greater in specific IgE SE seropositive patients. The multivariate linear regression analysis showed two significant associations of specific IgE SE seropositivity. We found a negative with FEV1% pred with beta standardized coefficient 95%CI −0.054 (−0.083, −0.031), p < 0.001, and a positive with SMA with beta standardized coefficient 95%CI 0.054 (0.081, 0.037), p < 0.001. Conclusions: Seropositivity to specific IgE SEs in severe asthma is associated with more severe airflow limitation, obstruction, and upregulation in SMA, indicating a possible role in the remodeling process. [ABSTRACT FROM AUTHOR]

Objectives: Exposure to benzo[α]pyrene (BaP) increases the incidence and severity of allergic rhinitis (AR), but the underlying mechanisms remain unclear. Thus, we investigated the in vivo effects of BaP exposure on mucus hypersecretion and tissue remodeling in a rat model of AR. Methods: Female Sprague–Dawley rats were randomly divided into 4 groups: a negative control group, a group of healthy rats exposed to BaP, a group of rats with ovalbumin (OVA)-induced AR, and a group of AR model rats exposed to BaP. Nasal symptoms and levels of OVA-specific serum immunoglobulin E (IgE) were measured in each individual rat. Moreover, examination of goblet cell hyperplasia and collagen deposition was carried out with periodic acid-Schiff (PAS) staining and Masson trichrome (MT) staining. Mucin 5AC (MUC5AC) expression was assessed by immunohistochemistry. Results: BaP significantly increased the number of sneezes, the number of nasal rubs and the levels of OVA-specific serum IgE in rats with AR. Statistically significant differences in goblet cell hyperplasia and collagen deposition were observed between the BaP-exposed AR model group and the AR model group. Immunohistochemical results showed that the nasal mucosa of AR model rats displayed markedly elevated MUC5AC expression after BaP exposure. Conclusion: Our data indicate that mucus hypersecretion and the development of nasal remodeling might be pathophysiologic mechanisms underlying increased susceptibility to AR after exposure to BaP. [ABSTRACT FROM AUTHOR]

Background: Skeletal muscles are vital for daily function, yet assessing their injuries remain challenging. We aimed to elucidate the effectiveness of 68Ga-FAPI-04 in evaluating skeletal muscle remodeling. Results: C2C12 cells were subjected to graded H2O2 stimulation in vitro, revealing an initial rise and subsequent decline in fibroblast activation protein (FAP) expression as H2O2 concentration increased. In vivo, a murine triceps surae injury model was created using various solutions to simulate normal repair, mild repair failure, and severe repair failure. Assessments were conducted on days 1, 3, 7, and 14 using PET, MRI, and ultrasound. With 68Ga-FAPI-04, the normal and mild repair failure groups showed significantly higher SUVmax and T/B ratios on day 1 compared to the severe repair failure group. These values gradually decreased in the normal repair group, becoming negligible after day 7. MRI results for the normal repair group showed low to moderate signal intensity by day 7. A clinical study retrospectively evaluated post-hip arthroplasty patient images at intervals of 1 month, 2–3 months, 5–6 months, and over 7 months. In these patients, 18F-FDG SUVmax and volume remained relatively stable over time, while 68Ga-FAPI-04 SUVmax initially increased, then decreased, with a consistent reduction in volume. Conclusion: In skeletal muscle injuries, FAP demonstrates a distinctive mechanism of action, and 68Ga-FAPI-04, in comparison to other tests, more precisely captures alterations in lesion site uptake intensity and volume. Trial registration: Trial registration: ChiCTR2000041204. Registered 22 December 2020, https://www.chictr.org.cn/showproj.html?proj=66211 [ABSTRACT FROM AUTHOR]

There are significant sex and age differences in left ventricular (LV) remodeling that may lead to disparity in outcomes when used to inform the timing of aortic regurgitation (AR) intervention. The aim of this study was to examine whether left atrial (LA) parameters might represent better criteria than LV parameters to inform the timing of AR intervention. Using data on patients with moderate to severe or severe AR with serial echocardiography (2010-2016), the longitudinal trends in left atrial volume index (LAVI) and left atrial reservoir strain (LAr) were evaluated by sex and age. The incremental utility of these parameters in predicting adverse events over LV parameters was also determined. In 525 patients (25.7% women) with 1,687 echocardiograms over a median follow-up period of 2.0 years (Q1-Q3: 1.0-3.6 years), there was significant increase in LAVI (1.0 mL/m2 per year [95% CI: 0.76-1.2 mL/m2 per year]) and decrease in LAr (−1.3% per year [95% CI: −1.6% to −0.92%]), without a significant interaction by sex or age category (P for interaction ≥ 0.17). In addition, both LAVI and LAr were significant predictors of adverse events independent of LV parameters. The optimal discriminatory thresholds were 37 mL/m2 for LAVI and 35% for LAr. These thresholds were similar across categories of sex and age. Within the relatively short-term follow-up, surgery was associated with survival benefit among patients with LAVI ≥37 mL/m2 (HR: 0.33 [95% CI: 0.15-0.72]; P = 0.006) but was not statistically significant among patients with LAVI <37 mL/m2 (HR: 0.46 [95% CI: 0.18-1.17]; P = 0.09). Similarly, surgery was associated with survival for the subgroup with LAr ≤35% but not among those with LAr >35%. Unlike LV remodeling, LA remodeling demonstrates a similar rate of progression between categories of sex and age among patients with AR. In addition, LA parameters provide incremental prognostic value over LV parameters. [Display omitted] [ABSTRACT FROM AUTHOR]

Thoracic endovascular aortic repair (TEVAR) represents optimal therapy for complicated acute type B aortic dissection (aTBAD). Persistent knowledge gaps remain, including the optimal length of aortic coverage, impact on distal aortic remodeling, and fate of the dissected abdominal aorta. Review of the Emory Aortic Database identified 92 patients who underwent TEVAR for complicated aTBAD from 2012 to 2018. Standard TEVAR covered aortic zones 3 and 4 (from the left subclavian to the mid-descending thoracic aorta). Extended TEVAR fully covered aortic zones 3 though 5 (from the left subclavian to the celiac artery). Long-term imaging, clinical follow-up, and overall and aortic-specific mortality were reviewed. Extended TEVAR (n = 52) required a greater length of coverage vs standard TEVAR (n = 40) (240 ± 32 mm vs 183 ± 23 mm; P <.01). In-hospital mortality occurred in 5.4% of patients (7.7% vs 2.5%; P =.27) owing to mesenteric malperfusion (n = 3) or rupture (n = 2). The overall incidences of postoperative stroke, transient paraparesis, paraplegia, and dialysis were 5.4% (3.9% vs 7.5%; P =.38), 3.2% (5.8% vs 0%; P =.18), 0%, and 0% respectively, equivalent between groups. Follow-up was 96.6% complete to a mean of 6.1 years (interquartile range, 3.5-8.6 years). There were significantly higher rates of complete thrombosis or obliteration of the entire thoracic false lumen after Extended TEVAR (82.2% vs 51.5%; P =.04). Distal aortic reinterventions were less frequent after extended TEVAR (5.8% vs 20%; P =.04). Late aorta-specific survival was 98.1% after extended TEVAR vs 92.3% for standard TEVAR (P =.32). Extended TEVAR for complicated aTBAD is safe, results in a high rate of total thoracic false lumen thrombosis/obliteration, and reduces distal reinterventions. Longer-term follow-up will be needed to demonstrate a survival benefit compared to limited aortic coverage. [ABSTRACT FROM AUTHOR]

Coupling, the mechanism that controls the sequence of events in bone remodeling, is a fundamental theory for understanding the way the skeleton changes throughout life. This review is an adapted version of the Louis V Avioli lecture, delivered at the Annual Scientific Meeting of the American Society of Bone and Mineral Research in 2023. It outlines the history of the coupling concept, details how coupling is thought to occur within trabecular and cortical bone, and describes its multiple contexts and the many mechanisms suggested to couple bone-forming osteoblasts to the prior action of osteoclasts on the same bone surface. These mechanisms include signals produced at each stage of the remodeling sequence (resorption, reversal, and formation), such as factors released by osteoclasts through their resorptive action and through protein synthesis, molecules deposited in the cement line during the reversal phase, and potential signals from osteocytes within the local bone environment. The review highlights two examples of coupling factors (Cardiotrophin 1 and EphrinB2:EphB4) to illustrate the limited data available, the need to integrate the many functions of these factors within the basic multicellular unit (BMU), and the multiple origins of these factors, including the other cell types present during the remodeling sequence (such as osteocytes, macrophages, endothelial cells, and T-cells). Lay Summary: Coupling is a fundamental process by which bone-resorbing cells (osteoclasts) are followed by bone-forming cells (osteoblasts) on the same surface during the process of bone remodeling. This review outlines the history, basic concepts, and mechanisms proposed, and suggests directions for further research into the way this sequence of events is controlled in bone maintenance, development, and healing. [ABSTRACT FROM AUTHOR]

Wounds are the common fates in various microbial infections and physical damages including accidents, surgery, and burns. In response, a healthy body with a potent immune system heals that particular site within optimal time by following the coagulation, inflammation, proliferation, and remodeling phenomenon. However, certain malfunctions in the body due to various diseases particularly diabetes and other physiological factors like age, stress, etc., prolong the process of wound healing through various mechanisms including the Akt, Polyol, and Hexosamine pathways. The current review thoroughly explains the wound types, normal wound healing mechanisms, and the immune system's role. Moreover, the mechanistic role of diabetes is also elaborated comprehensively. Comparative analysis of the molecular events during different wound healing phases in healthy and diabetic/stressed/aged individuals. [ABSTRACT FROM AUTHOR]

Doxorubicin‐based chemotherapy is a widely used first‐line treatment for breast cancer, yet it is associated with various side effects, including splenic atrophy. However, the pathogenic mechanisms underlying doxorubicin‐induced atrophy of the spleen remain unclear. This study investigates that doxorubicin treatment leads to splenic atrophy through several interconnected pathways involving histological changes, an inflammatory response, and apoptosis. Immunohistochemical and western blot analyses revealed reduced size of white and red pulp, decreased cellularity, amyloidosis, and fibrotic remodeling in the spleen following doxorubicin treatment. Additionally, increased secretion of pro‐inflammatory cytokines was detected using an antibody array and enzyme‐linked immunosorbent assay (ELISA), which triggers inflammation through the regulation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor‐kappa B (NF‐κB) signaling pathways. Further analysis revealed that the loss of regulators and effectors of the oxidative defense system, including sirtuin (Sirt)3, Sirt5, superoxide dismutase (SOD)1, and SOD2, was implicated in the upstream regulation of caspase‐dependent cellular apoptosis. These findings provide insights on the pathogenic mechanisms underlying doxorubicin‐induced splenic atrophy and suggest that further investigation may be warranted to explore strategies for managing potential side effects in breast cancer patients treated with doxorubicin. Doxorubicin, a common breast cancer treatment, induces splenic atrophy through interconnected pathways. This study reveals that doxorubicin causes white and red pulp shrinkage, cellular depletion, and fibrosis. Elevated pro‐inflammatory cytokines trigger inflammation via STAT3 and NF‐κB pathways. Downregulation of oxidative defense regulators (Sirt3, Sirt5, SOD1, and SOD2) contributes to caspase‐dependent apoptosis. These findings elucidate the mechanisms of doxorubicin‐induced splenic atrophy, highlighting the need for strategies to mitigate side effects in breast cancer patients. [ABSTRACT FROM AUTHOR]

Alveolar bone remodeling during the retention phase is essential for successful orthodontic treatment. Pulsed electromagnetic field (PEMF) therapy is an adjunctive therapy for bone-related diseases that induces osteogenesis and prevents bone loss. This study aimed to examine the role of PEMF exposure during the retention phase of orthodontic treatment in alveolar bone remodeling. A total of 36 male Wistar rats were divided into control, PEMF 7, and PEMF 14 groups; a 50 g force nickel–titanium closed-coil spring was inserted to create mesial movement in the first molar for 21 d. Furthermore, the spring was removed, and the interdental space was filled with glass ionomer cement. Concurrently, rats were exposed to a PEMF at 15 Hz with a maximum intensity of 2.0 mT 2 h daily, for 7 and 14 days. Afterwards, the cements were removed and the rats were euthanized on days 1, 3, 7, and 14 to evaluate the expression of Wnt5a mRNA and the levels of RANKL, OPG, ALP, and Runx2 on the tension side. The data were analyzed with ANOVA and post hoc tests, with p < 0.05 declared statistically significant. PEMF exposure significantly upregulated Wnt5a mRNA expression, OPG and ALP levels, and Runx2 expression, and decreased RANKL levels in the PEMF 7 and 14 groups compared to the control group (p < 0.05). This study showed that PEMF exposure promotes alveolar bone remodeling during the orthodontic retention phase on the tension side by increasing alveolar bone formation and inhibiting resorption. [ABSTRACT FROM AUTHOR]

Abstract Background Skeletal muscles are vital for daily function, yet assessing their injuries remain challenging. We aimed to elucidate the effectiveness of 68Ga-FAPI-04 in evaluating skeletal muscle remodeling. Results C2C12 cells were subjected to graded H2O2 stimulation in vitro, revealing an initial rise and subsequent decline in fibroblast activation protein (FAP) expression as H2O2 concentration increased. In vivo, a murine triceps surae injury model was created using various solutions to simulate normal repair, mild repair failure, and severe repair failure. Assessments were conducted on days 1, 3, 7, and 14 using PET, MRI, and ultrasound. With 68Ga-FAPI-04, the normal and mild repair failure groups showed significantly higher SUVmax and T/B ratios on day 1 compared to the severe repair failure group. These values gradually decreased in the normal repair group, becoming negligible after day 7. MRI results for the normal repair group showed low to moderate signal intensity by day 7. A clinical study retrospectively evaluated post-hip arthroplasty patient images at intervals of 1 month, 2–3 months, 5–6 months, and over 7 months. In these patients, 18F-FDG SUVmax and volume remained relatively stable over time, while 68Ga-FAPI-04 SUVmax initially increased, then decreased, with a consistent reduction in volume. Conclusion In skeletal muscle injuries, FAP demonstrates a distinctive mechanism of action, and 68Ga-FAPI-04, in comparison to other tests, more precisely captures alterations in lesion site uptake intensity and volume. Trial registration Trial registration: ChiCTR2000041204. Registered 22 December 2020, https://www.chictr.org.cn/showproj.html?proj=66211

Introduction: Left ventricular hypertrophy (LVH) is a relevant sign associated with an increased risk of sudden death. The causes of LVH including cardiac amyloidosis (CA), Fabry disease (FD), hypertrophic cardiomyopathy (HCM) are associated with an inauspicious prognosis. Transthoracic echocardiography (TTE) remains the first-step baseline diagnostic method. Material and methods: A retrospective one-center analysis of 86 patients (pts) with increased left ventricular (LV) wall thickness in TTE was performed. The inclusion criteria were interventricular septum (IVS) above 10 mm in males, 9 mm in females and the final diagnosis of CA, FD or HCM. The study population was divided into three subgroups: CA (13 pts), FD (7 pts), HCM (66 pts). The LV mass index (LVMI), relative wall thickness (RWT) and type of remodeling were analyzed. Results: Increased LVMI occurred in 90.9% pts with CA, all with FD, 89.5% with HCM.RWT exceeded the normal range among 92.3% pts with CA, 57.1% with FD, 92.4% with HCM. Concentric hypertrophy was diagnosed in 75% pts with CA, 57.1% with FD, 84.2% with HCM and eccentric in 8.3% pts with CA, 42.9% with FD, 5.3% with HCM (p = 0.01). An abnormal IVS/PWT index was observed in 23.1% pts with CA, 28.6% with FD, 79.7% with HCM (p = 0.00001). Conclusions: Although cardiac hypertrophy is a typical sign, it does not occur in all subjects with CA, FD, HCM. More detailed analysis including the form of hypertrophy as well as left atrium remodeling are required to be characterized for specific diseases: CA, FD, HCM. Asymmetrical hypertrophy is more specific for HCM.

Background. Chronic lymphocytic leukemia (CLL) is the second most common hematological malignancy without a trend towards a decrease in its incidence. 66 % of patients with CLL experience bone fractures as a result of osteoporosis in all age groups, and the detection frequency is no more than 15 %. Insufficient understanding of the osteoporosis pathogenesis in CLL leads to problems in diagnosis, prevention and therapy.The aim of the study. To analyze modern data on the features of the osteoporosis pathogenesis in chronic lymphocytic leukemia.Results and discussion. Osteoporosis is formed when osteoresorption prevails over osteosynthesis due to intercellular interactions of bone tissue and the immune system, dysregulation of intracellular signaling pathways RANKL/RANK/OPG, Wnt, FoxO, RUNX2, initiated by cytokines, growth factors, prostaglandins, and hormones. The degree of osteoresorption in CLL is associated with the severity of the clinical course, chemotherapy and hormonal deprivation. The osteoporosis pathogenesis in CLL is considered as part of a complex set of events, including, firstly, the interaction between leukemic cells (overexpression of PTHrP, RANKL) and bone cells (synthesis of growth factors), which forms a vicious circle of osteoresorption and tumor growth. Secondly, pro-inflammatory markers in CLL (tumor necrosis factor α, interleukin (IL) 1β, IL-6, IL-8, IL-11, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, transforming growth factor β, prostaglandin E2) limit osteoblast-induced osteosynthesis and stimulate the expansion of osteoclasts from monocytic suppressor cells of myeloid origin with or without the participation of the RANKL/RANK system. Thirdly, oxidative stress in CLL and impaired efficiency of antioxidant protection with the participation of fibroblast growth factor 23, transcription factor Nrf-2 with activation of JNK, ERK1/2, NF-κB, and also an increase in the RANKL/OPG ratio lead to inhibition of osteoblastogenesis.Conclusion. Analyzing and systematizing data on the osteoporosis pathogenesis in CLL are instrumental for the development of diagnostic criteria for osteoporosis in chronic lymphocytic leukemia that are much-needed in clinical practice and for the improvement of therapeutic tactics.

BACKGROUND: Acute myocardial infarction can cause cardiac remodeling and heart failure, as well as skeletal myopathy, affecting patients' quality of life. Exercise therapy is an important rehabilitation method for patients with heart failure; however, the optimal exercise prescription has not been clarified. OBJECTIVE: To compare the effects of different exercise modes (aerobic exercise, resistance exercise) on skeletal muscle remodeling in rats with acute myocardial infarction induced heart failure and to explore the possible mechanism, so as to provide a basis for optimizing the exercise rehabilitation program. METHODS: Forty-eight Sprague-Dawley rats were randomly divided into sham operation group, myocardial infarction group, aerobic exercise group and resistance exercise group. Coronary artery ligation was used to create model of heart failure. After 3 months, animals in the aerobic exercise group and resistance exercise group underwent 12 weeks of corresponding exercise mode interventions, while those in the sham operation group and myocardial infarction group were kept quietly in mouse cages. After the experiment, maximal running speed and maximal weight-bearing load were measured by graded treadmill exercise test and ladder-climbing test respectively, and heart structure and function were evaluated by echocardiography. The heart was isolated, and hematoxylin-eosin staining and Sirius red staining were performed to detect cardiac remodeling. For the gstrocnemius muscle, ATPase staining was performed to observe changes in muscle fiber type and cell cross-sectional area, dihydroethidium method was used to evaluate reactive oxygen species levels, enzymelinked immunosorbent method was used to determine malondialdehyde content and antioxidant enzyme activity, western blot was used to determine the expression of ubiquitin-proteasome system proteins, and the number of activated satellite cells (Pax7+ /MyoD+ ) were detected by double immunofluorescence staining. RESULTS AND CONCLUSION: (1) Exercise performance: Compared with the sham operation group, maximal running speed and maximal weight-bearing load in the myocardial infarction group decreased (P < 0.05); compared with the myocardial infarction group, the maximal running speed of the aerobic exercise group and the maximal weight-bearing load of the resistance exercise group increased (P < 0.05). (2) Cardiac remodeling: Compared with the sham operation group, infarction area, myocardial cell cross-sectional area, and collagen content in the myocardial infarction group increased (P < 0.05), while left ventricular ejection fraction and shortening fraction decreased (P < 0.05); compared with the myocardial infarction group, there was no statistical difference in the above parameters in both aerobic exercise resistance exercise groups (P > 0.05). (3) Skeletal muscle remodeling: Compared with the sham operation group, gastrocnemius muscle mass, gastrocnemius muscle mass index, cell cross-sectional area, superoxide dismutase activity, glutathione peroxidase activity, and the number of activated satellite cells decreased in myocardial infarction group (P < 0.05), while reactive oxygen species content, malondialdehyde content, and the protein expression of ubiquitin, MuRF1 and MAFbx increased (P < 0.05); compared with the myocardial infarction group, gastrocnemius muscle mass index, superoxide dismutase activity, the number of activated satellite cells increased in both aerobic exercise and resistance exercise groups (P < 0.05), while reactive oxygen species content and the protein expression of ubiquitin, MuRF1, and MAFbx decreased (P < 0.05); compared with the aerobic exercise group, gastrocnemius muscle mass, gastrocnemius muscle mass index, cell cross-sectional area, reactive oxygen species content, malondialdehyde content, the number of activated satellite cells increased in resistance exercise group (P < 0.05), while superoxide dismutase activity, glutathione peroxidase activity downregulated (P < 0.05). To conclude, aerobic exercise and resistance exercise can both improve exercise performance of rats with heart failure, and the mechanism is related to reducing oxidative stress, inhibiting ubiquitin-proteasome system activity and activating satellite cells to improve skeletal muscle remodeling. Aerobic exercise has a better effect on improving skeletal muscle oxidative stress, while resistance exercise has a more significant effect on promoting skeletal muscle regeneration. [ABSTRACT FROM AUTHOR]

Abstract Remodeling (re-engineering) of a tumor’s stroma has been shown to improve the efficacy of anti-tumor therapies, without destroying the stroma. Even though it still remains unclear which stromal component/-s and what characteristics hinder the reach of nanoparticles deep into cancer cells, we hypothesis that mechanisms behind stroma’s resistance to the penetration of nanoparticles rely heavily on extrinsic mechanical forces on stromal cells and cancer cells. Our hypothesis has been formulated on the basis of our previous study which has shown that changes in extracellular matrix (ECM) stiffness with tumor growth influence stresses exerted on fibroblasts and cancer cells, and that malignant cancer cells generate higher stresses on their stroma. This study attempts to establish a distinct identification of the components’ remodeling on the distribution and magnitude of stress within a tumor tissue which ultimately will impact the resistance of stroma to treatment. In this study, our objective is to construct a three-dimensional in silico model of a pancreas tumor tissue consisting of cancer cells, stromal cells, and ECM to determine how stromal remodeling alters the stresses distribution and magnitude within the pancreas tumor tissue. Our results show that changes in mechanical properties of ECM significantly alter the magnitude and distribution of stresses within the pancreas tumor tissue. Our results revealed that these stresses are more sensitive to ECM properties as we see the stresses reaching to a maximum of 22,000 Pa for softer ECM with Young’s modulus of 250 Pa. The stress distribution and magnitude within the pancreas tumor tissue does not show high sensitivity to the changes in mechanical properties of stromal cells surrounding stiffer cancer cells (PANC-1 with Young’s modulus of 2400 Pa). However, softer cancer cells (MIA-PaCa-2 with (Young’s modulus of 500 Pa) increase the stresses experienced by stiffer stromal cells and for stiffer ECM. By providing a unique platform to dissect and quantify the impact of individual stromal components on the stress distribution within a tumor tissue, this study serves as an important first step in understanding of which stromal components are vital for an efficient remodeling. This knowledge will be leveraged to overcome a tumor’s resistance against the penetration of nanoparticles on a per-patient basis.

Rationale: Surgical interventions have been recognized as the main method to repair of valvular disorders. Percutaneous transcatheter intervention with a clipping system is being actively introduced into the treatment of chronic heart failure (CHF) patients and mitral valve insufficiency (MVI) for correction of mitral regurgitation (MR), along with drug therapy. Aim: To establish the effect of the mitral valve leaflet clipping in the combination treatment of CHF patients on the clinical course of heart failure and the remodeling process. Methods: This single center prospective comparative study included 80 patients with CHF NYHA class II–IV and secondary MR grade 3–4. The patients were on optimal medical treatment (OMT) for CHF for at least 3 months before inclusion into the study. The main group included 55 patients who underwent transcatheter mitral valve repair with the use of MitraClip system, and the control group consisted of 25 patients in whom the surgery for MR was waived for various reasons (refusal of the surgery by the patient, some valve characteristics), and only OMT for CHF was used. At baseline, main clinical and demographic characteristics of the patients in the both groups were comparable. The duration of the follow-up was 6 months. Echocardiography (echoCG), a 6-minute walk test, and measurements of the brain natriuretic propeptide level were performed in all patients at baseline and at 6 months of the follow-up. Results: At 6 months, there was a significant reduction in CHF NYHA class and an increase in the 6-minute walk test distance and a decrease in diuretic requirements (converted to furosemide, from 58.4 ± 17.2 to 38.1 ± 20.7 mg daily, р = 0.02) in the group with the MitraClip implant, but not in the control group. In the OMT only group, there were no changes over 6 months in the diuretic requirements (48.1 ± 6.68 and 43.8 ± 27.15 mg daily, respectively, р = 0.8). The number of hospital readmissions due to CHF decompensation was 7 (12.7%) in the implanted MitraClip group and 4 (16%) in the OMT group (р = 0.69). EchoCG performed at 6 months after the surgical intervention identified no cases of MR grade 2. In the MitraClip implant group, there was a decrease in the size and volumes of the left atrium (р = 0.02 and р = 0.05, respectively), left ventricle (for end-diastolic diameter p = 0.002, end-diastolic volume p = 0.03), mean pulmonary artery pressure (p = 0.03), as well as an increase in cardiac output (р = 0.04). In the patients receiving OMT only, there were no significant changes in EchoCG parameters over time. Conclusion: Our study has shown benefits of the implantation of the mitral valve leaflet clipping system, compared to OMT only, in CHF. The clipping procedure promotes a significant improvement in clinical course of CHF, reverse myocardial remodeling, and reduction in diuretic requirements.

Abstract Background Rate control (RC; meanHRHolter ≤ 125 bpm) increases survival in dogs with atrial fibrillation (AF). The mechanisms remain unclear. Hypothesis/Objectives Investigate echocardiographic and biomarker differences between RC and non‐RC (NRC) dogs. Determine if changes post‐anti‐arrhythmic drugs (AAD) predict successful RC in subsequent Holter monitoring. Evaluate if early vs late RC affects survival. Animals Fifty‐two dogs with AF. Methods Holter‐derived mean heart rate, echocardiographic and biomarker variables from dogs receiving AAD were analyzed prospectively at each re‐evaluation and grouped into RC or NRC. The primary endpoint was successful RC. Between group comparisons of absolute values, magnitude of change from admission to re‐evaluations and end of study were performed using Mann‐Whitney tests or unpaired t‐tests. Logistic regression explored variables associated with inability to achieve RC at subsequent visits. Kaplan‐Meier survival analysis was used to compare survival time of early vs late RC. Results At visit 2, 11/52 dogs were RC; at visit 3, 14/52 were RC; and at visit 4, 4/52 were RC. At the end of study, 25/52 remained NRC. At visit 2, both groups had increased cardiac dimensions, but NRC dogs had larger dimensions; biomarkers did not differ. At the end of study, RC showed decreased cardiac dimensions and end‐terminal pro‐brain natriuretic peptide (NT‐proBNP) compared with NRC. No variables were useful at predicting RC success in subsequent visits. Survival analysis found no differences between early vs late RC. Conclusions and Clinical Importance The RC dogs had decreased cardiac dimensions and NT‐proBNP, suggesting HR‐mediated reverse‐remodeling might benefit survival, even with delayed RC achievement. Pursuit of RC is crucial despite initial failures.

Abstract Background Fibroblast differentiation to a myofibroblast phenotype is a feature of airway remodeling in asthma. Lung fibroblasts express the integrin receptor α4β7 and fibronectin induces myofibroblast differentiation via this receptor. Objectives To investigate the role of the β7 integrin receptor subunit and α4β7 integrin complex in airway remodeling and airway hyperresponsiveness (AHR) in a murine model of chronic allergen exposure. Methods C57BL/6 wild type (WT) and β7 integrin null mice (β7 -/-) were sensitized (days 1,10) and challenged with ovalbumin (OVA) three times a week for one or 4 weeks. Similar experiments were performed with WT mice in the presence or absence of α4β7 blocking antibodies. Bronchoalveolar (BAL) cell counts, AHR, histological evaluation, soluble collagen content, Transforming growth factor-β (TGFβ) and Interleukin-13 (IL13) were measured. Phenotype of fibroblasts cultured from WT and β7 -/- saline (SAL) and OVA treated mice was evaluated. Results Eosinophil numbers were similar in WT vs β7-/- mice. Prolonged OVA exposure in β7-/- mice was associated with reduced AHR, lung collagen content, peribronchial smooth muscle, lung tissue TGFβ and IL13 expression as compared to WT. Similar findings were observed in WT mice treated with α4β7 blocking antibodies. Fibroblast migration was enhanced in response to OVA in WT but not β7 -/- fibroblasts. α-SMA and fibronectin expression were reduced in β7-/- fibroblasts relative to WT. Conclusions The β7 integrin subunit and the α4β7 integrin complex modulate AHR and airway remodeling in a murine model of allergen exposure. This effect is, at least in part, explained by inhibition of fibroblast activation and is independent of eosinophilic inflammation.

Remodeling (re-engineering) of a tumor's stroma has been shown to improve the efficacy of anti-tumor therapies, without destroying the stroma. Even though it still remains unclear which stromal component/-s and what characteristics hinder the reach of nanoparticles deep into cancer cells, we hypothesis that mechanisms behind stroma's resistance to the penetration of nanoparticles rely heavily on extrinsic mechanical forces on stromal cells and cancer cells. Our hypothesis has been formulated on the basis of our previous study which has shown that changes in extracellular matrix (ECM) stiffness with tumor growth influence stresses exerted on fibroblasts and cancer cells, and that malignant cancer cells generate higher stresses on their stroma. This study attempts to establish a distinct identification of the components' remodeling on the distribution and magnitude of stress within a tumor tissue which ultimately will impact the resistance of stroma to treatment. In this study, our objective is to construct a three-dimensional in silico model of a pancreas tumor tissue consisting of cancer cells, stromal cells, and ECM to determine how stromal remodeling alters the stresses distribution and magnitude within the pancreas tumor tissue. Our results show that changes in mechanical properties of ECM significantly alter the magnitude and distribution of stresses within the pancreas tumor tissue. Our results revealed that these stresses are more sensitive to ECM properties as we see the stresses reaching to a maximum of 22,000 Pa for softer ECM with Young's modulus of 250 Pa. The stress distribution and magnitude within the pancreas tumor tissue does not show high sensitivity to the changes in mechanical properties of stromal cells surrounding stiffer cancer cells (PANC-1 with Young's modulus of 2400 Pa). However, softer cancer cells (MIA-PaCa-2 with (Young's modulus of 500 Pa) increase the stresses experienced by stiffer stromal cells and for stiffer ECM. By providing a unique platform to dissect and quantify the impact of individual stromal components on the stress distribution within a tumor tissue, this study serves as an important first step in understanding of which stromal components are vital for an efficient remodeling. This knowledge will be leveraged to overcome a tumor's resistance against the penetration of nanoparticles on a per-patient basis. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) arises from increased pulmonary vascular resistance due to contraction and remodeling of the pulmonary arteries. The structural changes include thickening of the smooth muscle layer from increased proliferation and resistance to apoptosis. The mechanisms underlying apoptosis resistance in PH are not fully understood. In cancer cells, high expression of aquaporin 1 (AQP1), a water channel, is associated with apoptosis resistance. We showed AQP1 protein was expressed in pulmonary arterial smooth muscle cells (PASMCs) and upregulated in preclinical PH models. In this study, we used PASMCs isolated from control male rats and the SU5416 plus hypoxia (SuHx) model to test the role of AQP1 in modulating susceptibility to apoptosis. We found the elevated level of AQP1 in PASMCs from SuHx rats was necessary for resistance to apoptosis and that apoptosis resistance could be conferred by increasing AQP1 in control PASMCs. In exploring the downstream pathways involved, we found AQP1 levels influence the expression of Bcl‐2, with enhanced AQP1 levels corresponding to increased Bcl‐2 expression, reducing the ratio of BAX to Bcl‐2, consistent with apoptosis resistance. These results provide a mechanism by which AQP1 can regulate PASMC fate. [ABSTRACT FROM AUTHOR]

The hierarchic assembly of fibrillar collagen into an extensive and ordered supramolecular protein fibril is critical for extracellular matrix function and tissue mechanics. Despite decades of study, we still know very little about the complex process of fibrillogenesis, particularly at the earliest stages where observation of rapidly forming, nanoscale intermediates challenges the spatial and temporal resolution of most existing microscopy methods. Using video rate scanning atomic force microscopy (VRS-AFM), we can observe details of the first few minutes of collagen fibril formation and growth on a mica surface in solution. A defining feature of fibrillar collagens is a 67-nm periodic banding along the fibril driven by the organized assembly of individual monomers over multiple length scales. VRS-AFM videos show the concurrent growth and maturation of small fibrils from an initial uniform height to structures that display the canonical banding within seconds. Fibrils grow in a primarily unidirectional manner, with frayed ends of the growing tip latching onto adjacent fibrils. We find that, even at extremely early time points, remodeling of growing fibrils proceeds through bird-caging intermediates and propose that these dynamics may provide a pathway to mature hierarchic assembly. VRS-AFM provides a unique glimpse into the early emergence of banding and pathways for remodeling of the supramolecular assembly of collagen during the inception of fibrillogenesis. [ABSTRACT FROM AUTHOR]

Aneurysmal rupture is associated with wall thinning, but the mechanism is poorly understood. This study aimed to characterize the three-dimensional wall-thickness distributions of unruptured intracranial aneurysms. Five aneurysmal tissues were investigated using micro-computed tomography. First, the wall thickness was related to the aneurysmal wall appearances during surgery. The median wall thicknesses of the translucent and non-translucent walls were 50.56 and 155.93 µm, respectively (p < 0.05) with significant variation in the non-translucent wall thicknesses (p < 0.05). The three-dimensional observations characterized the spatial variation of wall thicknesses. Thin walls showed a uniform thickness profile ranging from 10 to 40 µm, whereas thick walls presented a peaked thickness profile ranging from 300 to 500 µm. In transition walls, the profile undulated due to the formation of focal thin/thick spots. Overall, the aneurysmal wall thicknesses were strongly site-dependent and spatially varied by 10 to 40 times within individual cases. Aneurysmal walls are exposed to wall stress driven by blood pressure. In theory, the magnitude of wall stress is inversely proportional to wall thickness. Thus, the observed spatial variation of wall thickness may increase the spatial variation of wall stress to a similar extent. The irregular wall thickness may yield stress concentration. The observed thin walls and focal thin spots may be caused by excessive wall stresses at the range of mechanical failure inducing wall injuries, such as microscopic tears, during aneurysmal enlargement. The present results suggested that blood pressure (wall stress) may have a potential of acting as a trigger of aneurysmal wall injury. [ABSTRACT FROM AUTHOR]

Perivascular adipose tissue (PVAT) regulates vascular function due to its capacity to synthesize vasoactive products and its mechanical properties. PVATs most abundant cells are adipocytes, and their populations are maintained by the maturation of adipocyte progenitor cells (APC), which may play a pivotal role in the pathogenesis of cardiovascular diseases. However, the distribution of APC within PVAT depots, their potential variation in spatial location, and the influence of sex and age on their abundance remain unknown. We hypothesize that APC abundance in PVAT is affected by location, age, sex and that APC subtypes have specific spatial distributions. PVAT from thoracic and abdominal aorta, and mesenteric arteries, and AT from interscapular, gonadal, and subcutaneous depots from 13-week and 30-week-old females and males Pdgfrα-CreERT2 x LSLtdTomato mice (n = 28) were analyzed. Abdominal aorta PVAT had fewer progenitors than mesenteric PVAT and gonadal AT. Aging reduced the abundance of APC in the thoracic aorta but increased their numbers in mesenteric PVAT. Females had more APC than males in mesenteric PVAT and gonadal AT depots. APC exhibited unique spatial distribution in the aorta and mesenteric PVAT where they localized neighboring vasa vasorum and arteries. APC subtypes (APC1, APC2, APC3, diff APC) were identified in all PVAT depots. Thoracic aorta PVAT APC3 were located in the adventitia while diff APC were in the parenchyma. This study identified variability in APC populations based on depot, age, and sex. The distinctive spatial distribution and the presence of diverse APC subtypes suggest that they may contribute differently to cardiovascular diseases-induced PVAT remodeling. [ABSTRACT FROM AUTHOR]

Musculoskeletal injuries, including tendinopathies, present a significant clinical burden for aging populations. While the biological drivers of age‐related declines in tendon function are poorly understood, it is well accepted that dysregulation of extracellular matrix (ECM) remodeling plays a role in chronic tendon degeneration. Senescent cells, which have been associated with multiple degenerative pathologies in musculoskeletal tissues, secrete a highly pro‐inflammatory senescence‐associated secretory phenotype (SASP) that has potential to promote ECM breakdown. However, the role of senescent cells in the dysregulation of tendon ECM homeostasis is largely unknown. To assess this directly, we developed an in vitro model of induced cellular senescence in murine tendon explants. This novel technique enables us to study the isolated interactions of senescent cells and their native ECM without interference from age‐related systemic changes. We document multiple biomarkers of cellular senescence in induced tendon explants including cell cycle arrest, apoptosis resistance, and sustained inflammatory responses. We then utilize this in vitro senescence model to compare the ECM remodeling response of young, naturally aged, and induced‐senescent tendons to an altered mechanical stimulus. We found that both senescence and aging independently led to alterations in ECM‐related gene expression, reductions in protein synthesis, and tissue compositional changes. Furthermore, MMP activity was sustained, thus shifting the remodeling balance of aged and induced‐senescent tissues towards degradation over production. Together, this demonstrates that cellular senescence plays a role in the altered mechano‐response of aged tendons and likely contributes to poor clinical outcomes in aging populations. [ABSTRACT FROM AUTHOR]

Background: Fibroblast differentiation to a myofibroblast phenotype is a feature of airway remodeling in asthma. Lung fibroblasts express the integrin receptor α4β7 and fibronectin induces myofibroblast differentiation via this receptor. Objectives: To investigate the role of the β7 integrin receptor subunit and α4β7 integrin complex in airway remodeling and airway hyperresponsiveness (AHR) in a murine model of chronic allergen exposure. Methods: C57BL/6 wild type (WT) and β7 integrin null mice (β7 -/-) were sensitized (days 1,10) and challenged with ovalbumin (OVA) three times a week for one or 4 weeks. Similar experiments were performed with WT mice in the presence or absence of α4β7 blocking antibodies. Bronchoalveolar (BAL) cell counts, AHR, histological evaluation, soluble collagen content, Transforming growth factor-β (TGFβ) and Interleukin-13 (IL13) were measured. Phenotype of fibroblasts cultured from WT and β7 -/- saline (SAL) and OVA treated mice was evaluated. Results: Eosinophil numbers were similar in WT vs β7-/- mice. Prolonged OVA exposure in β7-/- mice was associated with reduced AHR, lung collagen content, peribronchial smooth muscle, lung tissue TGFβ and IL13 expression as compared to WT. Similar findings were observed in WT mice treated with α4β7 blocking antibodies. Fibroblast migration was enhanced in response to OVA in WT but not β7 -/- fibroblasts. α-SMA and fibronectin expression were reduced in β7-/- fibroblasts relative to WT. Conclusions: The β7 integrin subunit and the α4β7 integrin complex modulate AHR and airway remodeling in a murine model of allergen exposure. This effect is, at least in part, explained by inhibition of fibroblast activation and is independent of eosinophilic inflammation. [ABSTRACT FROM AUTHOR]

In patients with end-stage chronic obstructive pulmonary disease (COPD), severe pulmonary hypertension (PH) is frequently associated with less severe airway obstruction as compared to mild or no PH. However, the histologic correlate of this finding is not clear. We aimed to quantify remodeling of pulmonary arteries, airways, and parenchyma in random samples of explanted end-stage COPD lungs. We quantified remodeling of small pulmonary arteries, small airways, and the degree of emphysema (mean interseptal distance [MID]) with dedicated software. As primary objective, we compared COPD patients with severe PH (SevPH-COPD) with age- and sex-matched MildPH-COPD. For comparison, we also investigated COPD lungs with no PH (NoPH-COPD), idiopathic PAH (IPAH), and healthy donors. We included n = 17 SevPH-COPD (mPAP = 43 [39-45]mm Hg), n = 17 MildPH-COPD (mPAP = 28 [24-31]mm Hg), n = 5 NoPH-COPD (mPAP = 18 [16-19]mm Hg), n = 10 IPAH (mPAP = 72 [65-91]mm Hg), and n = 10 healthy donor lungs. SevPH-COPD versus MildPH-COPD was characterized by better preserved forced vital capacity (51% vs 40% predicted, p < 0.05), less emphysema (MID 169 µm vs 279 µm, p < 0.001), and less PAS-positive and CD45-positive mucosa cells (15% vs 22%, p = 0.063% and 5% vs 7%, p = 0.058) suggesting less airway inflammation. In COPD patients, intimal and medial thickening were strongly correlated with mPAP (r = 0.676, p < 0.001 and r = 0.595, p < 0.001). MID was negatively correlated with mPAP (r = −0.556, p < 0.001) and was highest in NoPH-COPD (mean 281 µm), suggesting that emphysema per se is not associated with PH. End-stage COPD with severe PH is characterized by pronounced pulmonary vascular remodeling, less inflammation of small airways, and less emphysema as compared to COPD with mild PH or no PH, suggesting that COPD with severe PH may represent a unique phenotype of COPD. [ABSTRACT FROM AUTHOR]

Background: Rate control (RC; meanHRHolter ≤ 125 bpm) increases survival in dogs with atrial fibrillation (AF). The mechanisms remain unclear. Hypothesis/Objectives: Investigate echocardiographic and biomarker differences between RC and non‐RC (NRC) dogs. Determine if changes post‐anti‐arrhythmic drugs (AAD) predict successful RC in subsequent Holter monitoring. Evaluate if early vs late RC affects survival. Animals: Fifty‐two dogs with AF. Methods: Holter‐derived mean heart rate, echocardiographic and biomarker variables from dogs receiving AAD were analyzed prospectively at each re‐evaluation and grouped into RC or NRC. The primary endpoint was successful RC. Between group comparisons of absolute values, magnitude of change from admission to re‐evaluations and end of study were performed using Mann‐Whitney tests or unpaired t‐tests. Logistic regression explored variables associated with inability to achieve RC at subsequent visits. Kaplan‐Meier survival analysis was used to compare survival time of early vs late RC. Results: At visit 2, 11/52 dogs were RC; at visit 3, 14/52 were RC; and at visit 4, 4/52 were RC. At the end of study, 25/52 remained NRC. At visit 2, both groups had increased cardiac dimensions, but NRC dogs had larger dimensions; biomarkers did not differ. At the end of study, RC showed decreased cardiac dimensions and end‐terminal pro‐brain natriuretic peptide (NT‐proBNP) compared with NRC. No variables were useful at predicting RC success in subsequent visits. Survival analysis found no differences between early vs late RC. Conclusions and Clinical Importance: The RC dogs had decreased cardiac dimensions and NT‐proBNP, suggesting HR‐mediated reverse‐remodeling might benefit survival, even with delayed RC achievement. Pursuit of RC is crucial despite initial failures. [ABSTRACT FROM AUTHOR]

Loss of proteostasis and cellular senescence have been previously established as characteristics of aging; however, their interaction in the context of lung aging and potential contributions to aging-associated lung remodeling remains understudied. In this study, we aimed to characterize endoplasmic reticulum (ER) stress response, cellular senescence, and their interaction in relation to extracellular matrix (ECM) production in lung fibroblasts from young (25–45 yr) and old (>60 yr) humans. Fibroblasts from young and old patients without significant preexisting lung disease were exposed to vehicle, MG132, etoposide, or salubrinal. Afterward, cells and cell lysates or supernatants were analyzed for ER stress, cellular senescence, and ECM changes using protein analysis, proliferation assay, and senescence-associated beta-galactosidase (SA-b-Gal) staining. At baseline, fibroblasts from aging individuals showed increased levels of ER stress (ATF6 and PERK), senescence (p21 and McL-1), and ECM marker (COL1A1) compared to those from young individuals. Upon ER stress induction and etoposide exposure, fibroblasts showed an increase in senescence (SA-b-Gal, p21, and Cav-1), ER stress (PERK), and ECM markers (COL1A1 and LUM) compared to vehicle. Additionally, IL-6 and IL-8 levels were increased in the supernatants of MG132- and etoposide-treated fibroblasts, respectively. Finally, the ER stress inhibitor salubrinal decreased the expression of p21 compared to vehicle and MG132 treatments; however, salubrinal inhibited COL1A1 but not p21 expression in MG132-treated fibroblasts. Our study suggests that ER stress response plays an important role in establishment and maintenance of a senescence phenotype in lung fibroblasts and therefore contributes to altered remodeling in the aging lung. NEW & NOTEWORTHY The current study establishes functional links between endoplasmic reticulum (ER) stress and cellular senescence per se in the specific context of aging human lung fibroblasts. Recognizing that the process of aging per se is complex, modulated by the myriad of lifelong and environmental exposures, it is striking to note that chronic ER stress may play a crucial role in the establishment and maintenance of cellular senescence in lung fibroblasts. [ABSTRACT FROM AUTHOR]

Signal transduction by G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immunoreceptors converge at the activation of phospholipase C (PLC) for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5- trisphosphate (IP3) and diacylglycerol (DAG). This is a point for second-messenger bifurcation where DAG via protein kinase C (PKC) and IP3 via calcium activate distinct protein targets and regulate cellular functions. IP3 signaling is regulated by multiple calcium influx and efflux proteins involved in calcium homeostasis. A family of lipid kinases belonging to DAG kinases (DGKs) converts DAG to phosphatidic acid (PA), negatively regulating DAG signaling and pathophysiological functions. PA, through a series of biochemical reactions, is recycled to produce new molecules of PIP2. Therefore, DGKs act as a central switch in terminating DAG signaling and resynthesis of membrane phospholipids precursor. Interestingly, calcium and PKC regulate the activation of α and ζ isoforms of DGK that are predominantly expressed in airway and immune cells. Thus, DGK forms a feedback and feedforward control point and plays a crucial role in fine-tuning phospholipid stoichiometry, signaling, and functions. In this review, we discuss the previously underappreciated complex and intriguing DAG/DGK-driven mechanisms in regulating cellular functions associated with asthma, such as contraction and proliferation of airway smooth muscle (ASM) cells and inflammatory activation of immune cells. We highlight the benefits of manipulating DGK activity in mitigating salient features of asthma pathophysiology and shed light on DGK as a molecule of interest for heterogeneous diseases such as asthma. [ABSTRACT FROM AUTHOR]

A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1–2 μm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity. [ABSTRACT FROM AUTHOR]

Remodeling aging structures is common to enhance their structural, economic, and functional performance. However, the exceeding of bearing capacity of existing piles caused by increased upper loads due to vertical expansion frequently hinders their revitalization. In this paper, a methodology is proposed to control the demand-tocapacity ratio of existing piles without retrofitting the foundation, which is often accompanied by technical limitations and safety issues. A total of 12 tests were performed on four full-scale specimens, with tendon shape, wall thickness, boundary condition, and construction sequence as variables. Factors affecting load-transfer performance were identified based on test results. The target loadtransfer pattern implemented in accordance with the tendon shape was confirmed. To verify the validity of the method, tests using tendon shape and wall thickness as variables were compared with results from finite element analysis. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to report the long-term outcomes of proximal thoracic endovascular aortic repair (TEVAR) for chronic Stanford type B aortic dissection (cTBAD). Methods: We retrospectively analyzed the clinical data of 48 cases of patients with cTBAD who underwent proximal TEVAR in Zhongshan Hospital Fudan University from January 2010 to September 2013. The preoperative and postoperative imaging examinations, overall survival rate, aortic-related survival rate, and freedom from reintervention rate data were collected to evaluate aortic remodeling and clinical outcomes. The enrolled patients received follow-up at 1, 3, 6, and 12 months following treatment and annually thereafter. Results: A total of 48 patients (mean age, 58.3 ± 10.6 years; men:women, 40:8) were included, of which 38 cases (79.2%) were uncomplicated dissection and 10 cases (20.8%) were complicated. The mean follow-up time was 48.7 ± 40 months (1–120 months). The mean time interval from the initial procedure to reintervention was 50.6 ± 32.7 months (11–98 months). The following changes were observed at preoperative versus last follow-up timepoints. Descending aortic level: true lumen, 19.2 ± 7.01 mm vs. 36.9 ± 9.53 mm (p < 0.001); false lumen, 30.47 ± 15.89 mm vs. 19.16 ± 15.33 mm (p < 0.001); maximum diameter, 49.67 ± 13.96 mm vs. 56.66 ± 14.95 mm (p = 0.018). Diaphragm level: true lumen, 16.24 ± 5.41 mm vs. 24.41 ± 8.04 mm (p < 0.001); false lumen, 12.37 ± 11.49 mm vs. 14.92 ± 12.25 mm (p = 0.196); and maximum diameter, 34 ± 7.81 mm vs. 38.04 ± 7.7 mm (p < 0.001). The freedom from reintervention rate was 81% in 5 years and 50.6% in 10 years. The overall 10-years survival rate was 83% (6 of 48), and the aortic-related survival rate was 92.3% (3 of 48). Conclusions: TEVAR is a safe and effective proximal repair intervention for cTBAD that can reliably induce the positive remodeling of the descending aorta. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is a leading cause of death worldwide. Few drugs hold the ability to depress cardiac electrical and structural remodeling simultaneously after MI, which is crucial for the treatment of MI. The aim of this study is to investigate an effective therapy to improve both electrical and structural remodeling of the heart caused by MI. Here, an "ion cocktail therapy" is proposed to simultaneously reverse cardiac structural and electrical remodeling post‐MI in rats and minipigs by applying a unique combination of silicate, strontium (Sr) and copper (Cu) ions due to their specific regulatory effects on the behavior of the key cells involved in MI including angiogenesis of endothelial cells, M2 polarization of macrophages and apoptosis of cardiomyocyte. The results demonstrate that ion cocktail treatment attenuates structural remodeling post‐MI by ameliorating infarct size, promoting angiogenesis in both peri‐infarct and infarct areas. Meantime, to some extent, ion cocktail treatment reverses the deteriorative electrical remodeling by reducing the incidence rate of early/delayed afterdepolarizations and minimizing the heterogeneity of cardiac electrophysiology. This ion cocktail therapy reveals a new strategy to effectively treat MI with great clinical translation potential due to the high effectiveness and safety of the ion cocktail combination. [ABSTRACT FROM AUTHOR]

For orthopedic implants, biocompatibility is essential to ensure that they integrate with biological systems without causing negative reactions or impairing tissue function. Orthopedic implants must be cellularly acceptable to interact with neighboring tissues, including muscle, cartilage, and bone. Implant materials should not cause cytotoxic reactions or inflammatory responses that might hinder healing or result in long-term inflammation. Progress in surface engineering and biomaterials science is discovering implants that work well with the body, benefiting patients in the long run. The biocompatibility of orthopedic implants, their interaction with surrounding tissues, and the potential for biological problems are all important aspects of their design and operation. Orthopedic implants must be successful and long-lasting to ensure biocompatibility, promote osseointegration (osteointegration), avoid biofilm development, and consider the patient's biological environment. This paper discusses biocompatibility in orthopedic implants, its advancements, and challenges. [ABSTRACT FROM AUTHOR]

Background Studies in mice and small patient subsets implicate metabolic dysfunction in cardiac remodeling in aortic stenosis, but no large comprehensive studies of human metabolism in aortic stenosis with long-term follow-up and characterization currently exist. Methods and Results Within a multicenter prospective cohort study, we used principal components analysis to summarize 12 echocardiographic measures of left ventricular structure and function pre-transcatheter aortic valve implantation in 519 subjects (derivation). We used least absolute shrinkage and selection operator regression across 221 metabolites to define metabolic signatures for each structural pattern and measured their relation to death and multimorbidity in the original cohort and up to 2 validation cohorts (N=543 for overall validation). In the derivation cohort (519 individuals; median age, 84 years, 45% women, 95% White individuals), we identified 3 axes of left ventricular remodeling, broadly specifying systolic function, diastolic function, and chamber volumes. Metabolite signatures of each axis specified both known and novel pathways in hypertrophy and cardiac dysfunction. Over a median of 3.1 years (205 deaths), a metabolite score for diastolic function was independently associated with post-transcatheter aortic valve implantation death (adjusted hazard ratio per 1 SD increase in score, 1.54 [95% CI, 1.25-1.90]; P

Asthma is a chronic inflammatory disease with many patients failing to respond appropriately to pharmacotherapy. Thus, virgin coconut oil (VCO) can be an alternative therapy. Guinea pigs were divided into control (Ctrl), chronic allergic lung inflammation (Asth), Asth treated with dexamethasone (Asth + dexa), and Asth supplemented with VCO (Asth + VCO4). The tested animals were sensitized and challenged with ovalbumin. Relaxation induced by arachidonic acid (AA) was impaired in Asth, and this reduction was prevented by VCO (p = 0.0004), indicating formation of relaxing prostanoids, or the decrease of cysteinyl-leukotrienes by VCO. Furthermore, a possible negative modulation of β receptors/BKCa pathway by TGF–β in Asth was prevented by VCO (p = 0.0073). Finally, in Asth, Masson’s trichrome staining revealed airway remodeling and immunohistochemistry showed increased TGF-β expression in the lungs of Asth (p

Background We hypothesized that analysis of serial ECGs could predict new‐onset atrial fibrillation (AF) more accurately than analysis of a single ECG by detecting the subtle cardiac remodeling that occurs immediately before AF occurrence. Our aim in this study was to compare the performance of 2 types of machine learning (ML) algorithms. Methods and Results Standard 12‐lead ECGs of patients selected by cardiologists between January 2010 and May 2021 were used for ML model development. Two ML models (single ECG and serial ECG) were developed using a light gradient boosting machine‐learning algorithm. Model performance was evaluated based on the area under the receiver operating characteristic curve, sensitivity, specificity, accuracy, and F1 score. We trained the ML models on 415 964 ECGs from 176 090 patients. When testing the 2 ML models using external validation data sets, the performance of the serial‐ML model was significantly better than that of the single‐ML model for predicting new‐onset AF (single‐ versus serial‐ML model: sensitivity 0.744 versus 0.810; specificity 0.742 versus 0.822; accuracy 0.743 versus 0.816; F1 score 0.743 versus 0.815; area under the receiver operating characteristic curve 0.812 versus 0.880; P

Background: Cardiac remodeling is an adverse phenomenon linked to heart failure (HF) progression. Cardiac remodeling could represent the real therapeutic goal in the treatment of patients with HF and reduced ejection fraction (HFrEF), being potentially reversed through different pharmacotherapies. Currently, there are well-established drugs such as ACEi/ARBs and β-blockers with anti-remodeling effects. More recently, ARNI effects on cardiac remodeling were also demonstrated; additional potential benefits of gliflozins remain non clearly demonstrated. Aim of study: To evaluate possible changes in cardiac remodeling in patients with HFrEF/HFmrEF in treatment with ARNI or ARNI plus SGLT2i and the potential benefit on cardiac remodeling of adding SGLT2i to ARNI. Methods: Between June 2021 and August 2023, 100 consecutive patients with HFrEF/HFmrEF underwent conventional and advanced echocardiography (TDI, 2DSTE): patients were therefore divided into three groups according to therapy with neither ARNI nor SGLT2i, just ARNI or both. After 3 months, all patients underwent echocardiographic follow-up. Results: After a 3 months of therapy, significant improvements were observed for LVEF, LVEDD, LVEDV, LVESV, LV mass, E/e’, LV GLS, TAPSE (ANOVA p

Rationale: Severe pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is currently defined by an elevated mean pulmonary arterial pressure and strongly elevated pulmonary vascular resistance >5 wood units. Clinically, these patients show a male predominance, and usually present with very severe dyspnea, severe hypoxemia, strongly decreased exercise capacity and poor prognosis, even though the clinical picture is frequently associated with less severe airflow obstruction. Explanted lung samples of patients with COPD and severe PH show severe remodeling of small pulmonary arterioles, predominantly in the intima and media of the vessels. In this concise review, we discuss the clinical and histopathological evidence of severe PH in COPD.