Search Results (7,793)

The nitric oxide (NO) pathway is a fundamental regulator of vascular tone, myocardial function, and inflammation. In heart failure (HF), especially in advanced stages, dysregulation of NO–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signaling contributes to endothelial dysfunction, increased vascular resistance, myocardial fibrosis, and impaired cardiac performance. Chronic inflammation further reduces NO bioavailability, exacerbating HF progression This review synthesizes current knowledge on the role of the NO pathway in HF pathophysiology, with a focus on stable and advanced HF. Special attention is given to patient subgroups with comorbidities such as chronic kidney disease, where modulation of NO signaling may be particularly beneficial. We also evaluate therapeutic strategies targeting NO bioavailability and sGC stimulation. Evidence shows that impaired NO signaling promotes systemic and pulmonary vasoconstriction, elevates ventricular afterload, and worsens cardiac remodeling. Pharmacological agents that restore NO levels or activate downstream effectors such as sGC improve vasodilation, reduce fibrosis, and enhance myocardial relaxation. These effects are especially relevant in advanced HF patients and those with renal impairment, who often exhibit limited responses to conventional therapies. The NO pathway represents a promising therapeutic target in both stable and advanced HF. Modulating this pathway could improve outcomes, particularly in complex populations with multiple comorbidities, highlighting the need for further clinical research and tailored treatments. Full article

Circular RNAs are a class of stable non-coding RNAs generated through a back-splicing mechanism. They are now recognized as central players in cell function and are no longer considered byproducts of transcription. CircRNAs regulate gene expression at the transcriptional, post-transcriptional, and translational levels by interacting with various molecules. They act as sponges for miRNAs and proteins, molecular scaffolds, and can also be translated into peptides. Although advances in next-generation sequencing and PCR methods have improved their identification and quantification, technical and bioinformatic challenges remain. Increasing evidence shows their involvement in cardiovascular diseases such as heart failure, hypertrophy, fibrosis, and atherosclerosis, with protective or deleterious effects depending on the context. Given their presence in biological fluids and extracellular vesicles, they can be considered promising biomarkers, but their therapeutic applications are still under investigation. Future studies including a better understanding of their mechanisms of action, the development of standardized validation methods, and potential clinical applications (prevention, early diagnosis, personalized therapies) in diseases are still needed. This review provides an updated overview of the knowledge regarding circRNAs and their translational role in health and disease with a particular focus on cardiovascular diseases. Full article

Asthma is a chronic inflammatory disease with a heterogeneous course, often progressing silently from mild symptoms to severe, treatment-refractory disease. Current guidelines recommend biologic therapies after failure of high-dose inhaled corticosteroids and additional controllers, typically in patients with frequent exacerbations. This reactive approach may delay intervention until irreversible airway remodeling has occurred, limiting the potential benefits of biologic therapy. Therefore, severe asthma may be envisioned as the consequence of missed opportunities for early interventions. Early initiation of biologic therapy—guided by biomarkers such as blood eosinophil count and fractional exhaled nitric oxide (FeNO), as well as symptom burden and risk of lung function decline—may prevent progression to severe asthma and improve remission rates. This position paper advocates for a shift from severity-based to risk-based treatment strategies, recommending earlier biomarker assessment, redefinition of escalation criteria, and clinical trials designed to evaluate biologics in symptomatic non-exacerbating patients. By recognizing persistent inflammation and progression risk earlier in the disease course, clinicians may have a critical opportunity to alter the trajectory of asthma, reduce long-term morbidity, and achieve sustained control before irreversible damage occurs. Full article

Treatment for acute liver failure (ALF) is constrained by shortages of liver transplant donors and immune rejection. Porcine bone marrow mesenchymal stem cells (pBMSCs) demonstrate clinical potential in xenotransplantation due to their abundant availability, low immunogenicity, and strong proliferative activity. This study is the first to investigate the reparative effects and mechanisms of pBMSCs derived from Luopan Mountain pigs in a D-galactosamine (D-GalN)-induced ALF rat model. The results demonstrated that tail-vein transplantation of pBMSCs significantly improved survival rates in ALF rats; reduced serum ALT, AST, and TBIL levels; enhanced hepatic glycogen metabolism; and mitigated histopathological liver damage. Additionally, pBMSC transplantation upregulated serum HGF, IGF-1, and VEGF levels while inhibiting hepatocyte apoptosis. Mechanistic studies indicate that pBMSCs promote liver function recovery and regeneration by activating the PI3K/Akt/mTOR signaling pathway and suppressing its key negative regulator, PTEN, by regulating the expression of key genes involved in inflammation, fibrosis, proliferation, and apoptosis. This study provides crucial experimental evidence for the use of pBMSCs in treating acute liver failure (ALF) and lays the groundwork for its clinical translation in the field of xenotransplantation. Full article

Background/Clinical Significance: Development of acute antibody-mediated rejection (AMR) of allograft is one of the leading causes of mortality in heart-transplant recipients; however, the standard therapy does not always resolve severe forms of rejection. Extracorporeal photopheresis (ECP) is a method of immunomodulatory therapy that involves separating a patient’s white blood cells and treating them with a photosensitizer and ultraviolet A irradiation. Case Presentation: An 18-year-old female patient was urgently hospitalized with complaints of shortness of breath. She had undergone heart-transplant surgery 9 months before due to congenital heart disease restrictive cardiomyopathy, complicated with end-stage chronic heart failure. During the admission she admitted that for 3 weeks she discontinued tacrolimus and mycophenolate mofetil. AMR3 and CAV were verified. Conclusions: The use of standard approaches in the treatment of acute AMR is not always able to suppress an expressed immune reaction against the cardiac allograft, which leads to disruption of its function and rejection in the early or long-term follow-up. The inclusion of ECP in the treatment regimen allowed us to stabilize the patient’s condition and achieve regression in the severity of the AMR. It is believed that an important role in this was played by the activity of the immune system, which we assessed by changing the profile of cytokines, chemokines, and other growth factors. Thus, ECP demonstrated its effectiveness in the treatment of AMR of the cardiac allograft, with a change in the severity of the cytokine storm, as well as with an increase in the contribution of cytokines associated with the Th17 response. Full article

Background: Doxorubicin (Dox)-induced cardiotoxicity is the most important side effect of the drug and significantly limits its use in susceptible patients. Therefore, preventive measures are required to alleviate the Dox-induced cardiac failure. In this study, curcumin, a strong antioxidant agent, was investigated for its potential protective effect on dox-induced cardiotoxicity with its effect on Apelin expression as a mediator of cardiac function. Methods: Wistar albino rats were equally divided into four groups as Control, DOX, CUR, and CUR+DOX. Dox was administered a single dose of 20 mg/kg bw intraperitoneally while 100 mg/kg bw curcumin was given orally for 14 days before the Dox use. Results: DOX group showed a prolonged QT interval on an electrocardiogram and elevated cardiac troponin levels. In biochemical analyses, decreased Superoxide Dismutase activity and increased Malondialdehyde level and Catalase activity were detected in DOX group. Gene expression of Apelin decreased significantly while NF-κB increased in DOX group. Degenerative changes in histopathology, and increased iNOS and nitrotyrosine immunoreactivity were detected in DOX group. However, no significant changes were observed at reduced Glutathione, TNF-, and IL-1β levels. Curcumin use in Dox-given rats altered most of the disturbed parameters investigated in this study, indicating an alleviating effect on Dox-induced cardiotoxicity. Serum and heart Apelin levels and mRNA expression in heart tissue were detected to significantly increase in CUR+DOX group as compared to DOX group. Furthermore, NF-κB mRNA expression was significantly decreased in heart tissue of CUR+DOX group compared with the DOX group. Conclusions: The results suggest that Apelin acts as an important mediator in Dox cardiotoxicity and may be used as a target for treatment of certain cardiomyopathies. By regulating Apelin expression, curcumin may serve as a potential adjunct in cardioprotective approaches. Full article

The construction of large-scale infrastructure, such as power facilities, requires extensive use of reinforced concrete. The durability degradation of reinforced concrete structures in chloride environments involves multi-physics coupling effects, chloride ion diffusion, rebar corrosion, and concrete damage. Existing models neglect the coupling mechanisms among these processes and the influence of mesoscale structural characteristics. Therefore, this study proposes a diffusive–mechanical coupled phase field by integrating the phase field, chloride ion diffusion, and mechanical equivalence for rebar corrosion, establishing a multi-physics coupling analysis framework at the mesoscale. The model incorporates heterogeneous meso-structure of concrete and constructs a dynamic coupling function between the phase field damage variable and chloride diffusion coefficient, enabling full-process simulation of corrosion-induced cracking under chloride erosion. Numerical results demonstrate that mesoscale heterogeneity significantly affects crack propagation paths, with increased aggregate content delaying the initiation of rebar corrosion. Moreover, the case with corner-positioned rebar exhibits earlier cracking compared to the case with centrally located rebar. Furthermore, larger clear spacing delays delamination failure. Comparisons with the damage mechanics model and experimental data confirm that the proposed model more accurately captures tortuous crack propagation behavior, especially suitable for evaluating the durability of reinforced concrete components in facilities such as transmission tower foundations, substation structures, and marine power facilities. This research provides a highly accurate numerical tool for predicting the service life of reinforced concrete power infrastructure in chloride environments. Full article

Non-diabetic chronic kidney disease (ND-CKD) refers to the progressive and irreversible decline in kidney function occurring in the absence of diabetes mellitus—a distinction that sets it apart from the more prevalent diabetic CKD. While diabetic nephropathy remains the leading cause of CKD globally, ND-CKD encompasses a heterogeneous group of etiologies, including hypertensive nephrosclerosis, glomerulonephritis, and interstitial nephritis. Its incidence and prevalence are steadily increasing, particularly in aging populations, and are often underrecognized. Importantly, ND-CKD is not a benign entity; it independently contributes to systemic inflammation, oxidative stress, and metabolic dysregulation, which in turn amplify cardiovascular risk. Among the most severe complications is heart failure (HF), a complex syndrome arising from structural and functional impairments in cardiac performance. Despite ongoing advancements in HF management, mortality remains unacceptably high, ranging from 2–3% at 30 days to up to 50–75% over five years. Standard pharmacologic therapies frequently fall short in halting disease progression and may provoke undesirable side effects. This therapeutic gap has spurred growing interest in natural compounds with multi-targeted effects. Bioactive molecules such as arjunolic acid, kaempferol, luteolin, and resveratrol have shown anti-inflammatory and antioxidant properties that may offer dual benefits for both renal and cardiac function. By modulating shared molecular pathways—including those involved in inflammation, oxidative damage, and cellular dysfunction—these agents hold promise as adjunctive treatments in ND-CKD complicated by heart failure. Full article

This paper introduces Exponentiated Inverse Exponential Distribution (EIED), a novel probability model developed within the power inverse exponential distribution framework. A distinctive feature of EIED is its highly flexible hazard rate function, which can exhibit increasing, decreasing, and reverse bathtub (upside-down bathtub) shapes, making it suitable for modeling diverse lifetime phenomena in reliability engineering, survival analysis, and risk assessment. We derived comprehensive statistical properties of the distribution, including the reliability and hazard functions, moments, characteristic and quantile functions, moment generating function, mean deviations, Lorenz and Bonferroni curves, and various entropy measures. The identifiability of the model parameters was rigorously established, and maximum likelihood estimation was employed for parameter inference. Through extensive simulation studies, we demonstrate the robustness of the estimation procedure across different parameter configurations. The practical utility of EIED was validated through applications to real-world datasets, where it showed superior performance compared to existing distributions. The proposed model offers enhanced flexibility for modeling complex lifetime data with varying hazard patterns, particularly in scenarios involving early failure periods, wear-in phases, and wear-out behaviors. Full article

Advanced heart failure (AdHF) is a progressive condition with a high morbidity and mortality burden despite optimal medical therapy. Heart transplant (HT) and left ventricular assist device (LVAD) represent the only two life-prolonging options in AdHF. Unfortunately, only a minority of AdHF patients are eligible for these life-saving therapies, and even patients who are candidates for HT usually incur prolonged waiting list times. Intermittent or continuous home-based inotropic therapy offers a potential solution to improve quality of life, reduce recurrent hospitalizations, and maintain organ function, both for the stabilization of patients who are ultimately candidates for life-saving therapies and for palliative care in those without other therapeutic options. In this review, we summarize the current literature on the role of home inotropes in managing AdHF, emphasizing the current evidence on the most adopted agents, the practical considerations for their administration, and the possible different preferred utilization of these agents. Finally, we address gaps in the literature and outline future research directions to enhance therapeutic options and outcomes. Full article

Hemodynamic monitoring is fundamental in the management of critically ill patients with acute circulatory failure. The invasiveness of conventional devices, however, often limits their applicability in the emergency department (ED). Recent advances have introduced non-invasive modalities (including echocardiography, bioreactance, and plethysmography) that extend the use of hemodynamic assessment beyond the intensive care unit. Among various available techniques, bedside ultrasound (Point-of-Care Ultrasound, POCUS) emerges as a particularly versatile tool for rapid and comprehensive assessment of cardiac function and volume status. When integrated with continuous technologies such as bioreactance or pulse contour analysis, it allows for the adoption of more dynamic and personalized fluid management strategies. Currently, a multimodal and patient-centered approach represents the most effective paradigm for non-invasive hemodynamic evaluation in the emergency setting. This strategy enhances diagnostic accuracy and enables timely interventions guided by pathophysiological principles. Despite the inherent limitations of each technique, their integration provides emergency physicians with real-time information, with potential benefits on clinical outcomes and resource utilization. This review aims to outline the pathophysiological rationale for adopting non-invasive monitoring in the ED and to critically evaluate the advantages and limitations of each technique, providing emergency physicians with a concise framework to guide clinical practice. Full article

Normal concrete exhibits poor resistance to chloride penetration, often leading to reinforcement corrosion and premature structural failure. In contrast, ultra-high-performance concrete (UHPC) demonstrates superior resistance to corrosion caused by chloride salts. The chloride diffusion behaviour of UHPC was investigated via long-term immersion (LTI) and rapid chloride migration (RCM) tests. Additionally, this study presents the first development of a time-dependent diffusion model for UHPC under chloride corrosion, as well as the proposal of a performance-based design method for calculating the protective layer thickness. Results show that the incorporation of steel fibers reduced the chloride diffusion coefficient (D) by 37.9%. The free chloride content (FCC) in UHPC increased by 92.0% at 2 mm after 300 d of the action of LTI. D decreased by up to 91.0%, whereas the surface chloride concentration (C_s) increased by up to 92.5% under the action of LTI. The time-dependent models of D and C_s followed power and logarithmic functions, respectively. An increase in UHPC surface temperature, relative humidity, and tensile stress ratio significantly diminishes the chloride resistance of UHPC. The minimum UHPC protective layer thicknesses required for UHPC-HPC composite beams with design service lives of 100 years, 150 years, and 200 years are 30 mm, 37 mm, and 43 mm, respectively. Full article

Chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) are pathologies that impact mortality and morbidity worldwide. These chronic diseases have multiple causes, and they share some common clinical symptoms, such as diaphragm dysfunction (DD) and cognitive decline (CD), which, in turn, increase the mortality and morbidity rates in patients with COPD and CHF. One of the causes of CD is impaired glymphatic system function, with an accumulation of proteins and metabolites in the central nervous system. The glymphatic system is a structure that has not yet been widely considered by researchers and clinicians. Three key factors stimulate the ongoing physiological function of the glymphatic system: autonomic balance, heart rate, and, most importantly, the diaphragm. All these factors are altered in patients with COPD and CHF. This article reviews the relationship between the importance of the diaphragm, the glymphatic system, and CD, focusing on inspiratory rehabilitation training (IMT). Based on the data reported in this narrative review, we can strongly speculate that a consistent regimen of IMT in patients can improve cognitive status, reducing the cascade of symptoms that follow the diagnosis of CD. Further research is needed to understand whether targeting the glymphatic system with IMT is an effective option for helping patients delay the onset of CD. Full article

Background/Objectives: Patients with non-valvular heart failure frequently develop valvular disease. However, the prevalence of valvular disease across patients with different heart failure etiologies remains underexplored. This study aimed to investigate the burden of VHD among patients with non-valvular heart failure, and secondly evaluate its association with cardiopulmonary test. Methods: We analyzed data from patients with non-valvular heart failure (HF) who were evaluated as outpatients at the HF clinic between February 2020 and November 2024. Patients were categorized into three groups: coronary artery disease-related HF (CAD-HF), dilated cardiomyopathy (DCM), and other causes (e.g., hypertension, diabetes, and various cardiomyopathies). Demographic and clinical characteristics, as well as echocardiographic and cardiopulmonary exercise testing (CPET) results, were evaluated. Results: Among all groups mild mitral regurgitation (MR) was the most common valvular disease, followed by mild tricuspid regurgitation (TR). Patients with CAD-HF frequently had mild aortic regurgitation (AR) compared to DCM (23.6% vs. 14.9%, p = 0.05). In the CPET subgroup, which included 41 patients who consented to participate, in patients with moderate-to-severe VHD had significantly lower VO₂/HR (oxygen pulse), VO₂max, and OUES, indicating worsened functional capacity despite similar left ventricular ejection fraction. Hypertension and atrial fibrillation were independently associated with greater valvular disease severity on multivariable analysis. Conclusions: No significant differences in valvular disease between patients with DCM and CAD-HF were documented, apart from a higher prevalence of mild AR in the CAD-HF group. Patients with moderate-to-severe valvular regurgitation demonstrated worse cardiopulmonary performance, regardless of ejection fraction, highlighting the important role of CPET in evaluating the functional impact of valvular heart disease in this population. Full article

Background: Advanced heart failure (HF) carries high morbidity and mortality, and deterioration on the heart transplantation (HT) waiting list remains a major challenge. Intermittent outpatient levosimendan has been proposed as a bridge strategy, but the optimal regimen and its impact on peri-transplant outcomes remain uncertain. Within a personalized-medicine framework, we targeted a low-output/INTERMACS 3 phenotype and operationalized an adaptable, protocolized levosimendan pathway focused on perfusion/congestion stabilization to preserve transplant candidacy. Methods: We conducted a single-center, retrospective cohort study of 25 consecutive adults actively listed for HT between 2019 and 2024, treated with a standardized outpatient program of a 14-day interval of 6 h intravenous levosimendan infusions (target 0.2 μg/kg/min infusions) continued until transplant. Personalization in this program was operationalized through (i) phenotype-based eligibility (low CI and elevated filling pressures despite GDMT), (ii) predefined titration and safety rules for blood pressure, arrhythmias, and renal function, and (iii) individualized continuation until transplant with nurse-supervised monitoring and review of patient trajectories. Baseline characteristics, treatment exposure and safety, changes in hospitalizations and biomarkers, and peri-transplant outcomes were analyzed. Results: Patients were predominantly male (68%), with a mean age of 47.9 ± 17.5 years and severe LV dysfunction (LVEF 30.6 ± 9.8%). Median treatment duration was 131 days (IQR 60–241). No infusions required discontinuation for hypotension or arrhythmia, and no adverse events were directly attributed to levosimendan. Two patients (8%) died on the waiting list, both unrelated to therapy. During treatment, HF hospitalizations decreased significantly compared with the previous 6 months (48% vs. 20%, p = 0.033), renal function remained stable, and NT-proBNP trended downward. Of the 23 patients transplanted, two (9%) underwent urgent HT during decompensation. Post-transplant, vasoplegia occurred in 26% (n = 6 of 23), and 30-day mortality was 9% (n = 2 of 23). Conclusions: By defining the target phenotype, therapeutic goals, and adaptation rules, this study shows how a standardized but flexible outpatient levosimendan regimen can function as a personalized bridge strategy for low-output advanced HF. The approach was associated with fewer hospitalizations, stable renal function, and acceptable peri-transplant outcomes, and merits confirmation in multicenter cohorts with attention to patient heterogeneity and treatment effect refinement. Full article